Clin Pharmacokinet 2007; 46 (1): 13-58

REVIEW ARTICLE 0312-5963/07/0001-0013/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Clinical Pharmacokinetics and

Pharmacodynamics of Mycophenolate
in Solid Organ Transplant Recipients
Christine E. Staatz and Susan E. Tett
School of Pharmacy, University of Queensland, Brisbane, Queensland, Australia

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1. Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2. Current Dosing Guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
3. Clinical Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.1 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.2 Oral Bioavailability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.3 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.4 Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.5 Excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.6 Enterohepatic Recirculation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
4. Pharmacokinetic Parameter Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
5. Reasons for Pharmacokinetic Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.1 Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.2 Hepatic Impairment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.3 Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.4 Dialysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
5.5 Ethnicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.6 Gender . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.7 Co-Morbidities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.8 Hypoalbuminaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
5.9 Hyperbilirubinaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5.10 Time After Transplant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5.11 Interactions with Other Immunosuppressant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
5.12 Interactions with Other Co-Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.12.1 Resins and Binders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.12.2 Metal Ions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.12.3 Rifampicin (Rifampin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.12.4 Antacids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
5.12.5 Antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.12.6 St John’s Wort . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.12.7 Antibacterials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
5.13 Pharmacogenetic Variability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
6. Population Pharmacokinetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
7. Clinical Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
7.1 Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
7.2 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
8. Target Concentration Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
9. Estimation of Mycophenolic Acid Area Under the Concentration-Time Curve from 0 to 12 Hours 50
10. Pharmacodynamic Monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
14 Staatz & Tett

Abstract This review aims to provide an extensive overview of the literature on the
clinical pharmacokinetics of mycophenolate in solid organ transplantation and a
briefer summary of current pharmacodynamic information. Strategies are suggest-
ed for further optimisation of mycophenolate therapy and areas where additional
research is warranted are highlighted. Mycophenolate has gained widespread
acceptance as the antimetabolite immunosuppressant of choice in organ transplant
regimens. Mycophenolic acid (MPA) is the active drug moiety.
Currently, two mycophenolate compounds are available, mycophenolate
mofetil and enteric-coated (EC) mycophenolate sodium. MPA is a potent, selec-
tive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH),
leading to eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate
mofetil and EC-mycophenolate sodium are essentially completely hydrolysed to
MPA by esterases in the gut wall, blood, liver and tissue. Oral bioavailability of
MPA, subsequent to mycophenolate mofetil administration, ranges from 80.7% to
94%. EC-mycophenolate sodium has an absolute bioavailability of MPA of
approximately 72%.
MPA binds 97–99% to serum albumin in patients with normal renal and liver
function. It is metabolised in the liver, gastrointestinal tract and kidney by uridine
diphosphate gluconosyltransferases (UGTs). 7-O-MPA-glucuronide (MPAG) is
the major metabolite of MPA. MPAG is usually present in the plasma at 20- to
100-fold higher concentrations than MPA, but it is not pharmacologically active.
At least three minor metabolites are also formed, of which an acyl-glucuronide
has pharmacological potency comparable to MPA. MPAG is excreted into the
urine via active tubular secretion and into the bile by multi-drug resistance protein
2 (MRP-2). MPAG is de-conjugated back to MPA by gut bacteria and then
reabsorbed in the colon.
Mycophenolate mofetil and EC-mycophenolate sodium display linear
pharmacokinetics. Following mycophenolate mofetil administration, MPA maxi-
mum concentration usually occurs in 1–2 hours. EC-mycophenolate sodium
exhibits a median lag time in absorption of MPA from 0.25 to 1.25 hours. A
secondary peak in the concentration-time profile of MPA, due to enterohepatic
recirculation, often appears 6–12 hours after dosing. This contributes approxi-
mately 40% to the area under the plasma concentration-time curve (AUC). The
mean elimination half-life of MPA ranges from 9 to 17 hours.
MPA displays large between- and within-subject pharmacokinetic variability.
Dose-normalised MPA AUC can vary more than 10-fold. Total MPA concentra-
tions should be interpreted with caution in patients with severe renal impairment,
liver disease and hypoalbuminaemia. In such individuals, MPA and MPAG
plasma protein binding may be altered, changing the fraction of free MPA
available. Apparent oral clearance (CL/F) of total MPA appears to increase in
proportion to the increased free fraction, with a reduction in total MPA AUC.
However, there may be little change in the MPA free concentration. Ciclosporin
inhibits biliary excretion of MPAG by MRP-2, reducing enterohepatic recircula-
tion of MPA. Exposure to MPA when mycophenolate mofetil is given in combi-
nation with ciclosporin is approximately 30–40% lower than when given alone or
with tacrolimus or sirolimus. High dosages of corticosteroids may induce expres-
sion of UGT, reducing exposure to MPA. Other co-medications can interfere with
the absorption, enterohepatic recycling and metabolism of mycophenolate. Most
pharmacokinetic investigations of MPA have involved mycophenolate mofetil
rather than EC-mycophenolate sodium therapy.

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation 15

In population pharmacokinetic studies, MPA CL/F in adults ranges from 14.1

to 34.9 L/h (ciclosporin co-therapy) and from 11.9 to 25.4 L/h (tacrolimus
co-therapy). Patient bodyweight, serum albumin concentration and immunosup-
pressant co-therapy have a significant influence on CL/F.
The majority of pharmacodynamic data on MPA have been obtained in
patients receiving mycophenolate mofetil therapy in the first year after kidney
transplantation. Low MPA AUC is associated with increased incidence of biop-
sy-proven acute rejection. Gastrointestinal adverse events may be dose related.
Leukopenia and anaemia have been associated with high MPA AUC, trough
concentration and metabolite concentrations in some, but not all, studies. High
free MPA exposure has been identified as a risk factor for leukopenia in some
investigations. Targeting a total MPA AUC from 0 to 12 hours (AUC12) of 30–60
mg • hr/L is likely to minimise the risk of acute rejection and may reduce toxicity.
IMPDH monitoring is in the early experimental stage. Individualisation of
mycophenolate therapy should lead to improved patient outcomes. MPA AUC12
appears to be the most useful exposure measure for such individualisation.
Limited sampling strategies and Bayesian forecasting are practical means of
estimating MPA AUC12 without full concentration-time profiling. Target concen-
tration intervention may be particularly useful in the first few months post-trans-
plant and prior to major changes in anti-rejection therapy. In patients with
impaired renal or hepatic function or hypoalbuminaemia, free drug measurement
could be valuable in further interpretation of MPA exposure.

Mycophenolic acid (MPA) has gained wide-
spread acceptance as the antimetabolite immu-
nosuppressant of choice in solid organ transplant
regimens. An estimated 79% of kidney, 48% of liver
and 75% of heart transplant recipients are now pre-
scribed mycophenolate rather than azathioprine at
hospital discharge.[1] Currently, two mycophenolate
compounds are available: mycophenolate mofetil
and mycophenolate sodium. Following administra-
tion, both are rapidly hydrolysed to the active moie-
ty, MPA. It has been suggested that mycophenolate
usage may result in immunosuppression with a low-
er burden of toxicity than alternatives. This could be
achieved by allowing targeting of lower steady-state
calcineurin inhibitor concentrations, avoidance of
maintenance calcineurin inhibitor immunosuppres-
sion altogether through utilisation of combinations,
such as mycophenolate and sirolimus, and avoid-
ance or early withdrawal of corticosteroids from
treatment regimens.[2]
Mycophenolate mofetil is approved in the US for
prophylaxis of organ rejection in kidney, liver and
heart transplant recipients.[3] Its approval was initial-
ly based on data from three, randomised, double-
blind, controlled, multicentre phase III trials per-
formed in de novo kidney transplant recipients.[4-6]
Combination therapy consisting of mycophenolate
mofetil, ciclosporin and corticosteroids significantly
reduced acute rejection compared with combination
ciclosporin, corticosteroids and either placebo or
azathioprine treatment. Since then, mycophenolate
mofetil has proven effective with other immunosup-
pressant agents, such as tacrolimus and sirolimus,
and in other solid organ transplant groups. Enteric-
coated (EC) mycophenolate sodium is indicated for
kidney transplant recipients.[7] Its approval was
based on two randomised, double-blind, multicentre
trials comparing mycophenolate mofetil with EC
mycophenolate sodium in terms of safety and effica-
cy.[8] In 423 de novo renal transplant recipients, the
incidence of treatment failure was similar in EC
mycophenolate sodium and mycophenolate mofetil-
treated patients at 6 and 12 months post-trans-
plant.[9]
MPA is a potent, selective and reversible inhibi-
tor of inosine monophosphate dehydrogenase
(IMPDH), a key enzyme involved in the de novo
synthesis of guanine nucleotides.[10] T and B lym-

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (1)
16
phocytes are critically dependant on de novo synthe-
sis of purines for proliferation, whereas other cell
types can utilise salvage pathways.[10] MPA inhibits
the proliferative response of T and B lymphocytes to
both allospecific and mitogen stimulation, and sup-
presses antibody formation by B lymphocytes.[10]
MPA also depletes guanosine triphosphate, leading
to inhibition of glycosylation and reduced recruit-
ment of leukocytes to sites of inflammation.[10]
This article aims to provide the clinician with an
extensive overview of the literature on the clinical
pharmacokinetics of mycophenolate in solid organ
transplant recipients and a briefer summary of cur-
rent pharmacodynamic information. Strategies are
suggested for further optimisation of mycophenolate
therapy, and areas where additional research is like-
ly to be warranted are highlighted.
1. Formulations
Mycophenolate mofetil is the 2,4-morpholi-
noethyl ester of MPA. It was devised as a prodrug
because the oral bioavailability of MPA is relatively
low. Mycophenolate mofetil doses can be converted
to equivalent MPA content by multiplying by 0.739.
It is marketed by Roche Pharmaceuticals as
CellCept® 1. For oral administration, mycopheno-
late mofetil capsules (250mg), tablets (500mg) and a
powder for suspension (200 mg/mL when constitut-
ed) are available. For patients unable to swallow oral
medication, an intravenous formulation also exists.
This is supplied as a lyophilised powder in glass
vials containing the equivalent of mycophenolate
mofetil 500mg (mycophenolate mofetil hydrochlo-
ride 542mg).
Mycophenolate sodium is the sodium salt of
MPA. It is available for oral use as a delayed-release
tablet containing either 180mg or 360mg of MPA.
EC mycophenolate sodium is marketed by Novartis
Pharmaceuticals as Myfortic®. Two EC mycophe-
nolate sodium tablets 360mg (MPA 720mg) deliver
a near-equimolar dose of MPA as mycophenolate
mofetil 1g (MPA 739mg).
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
2. Current Dosing Guidelines
Currently, manufacturer guidelines for mycophe-
nolate dosage are standard for all individuals within
a transplant group.[3,7] In adult renal transplant recip-
ients, an oral dose of mycophenolate mofetil 1g
twice daily, or EC mycophenolate sodium 720mg
twice daily, is recommended.[3,7] In adult hepatic
transplant recipients, mycophenolate mofetil 1g
twice daily administered intravenously, or 1.5g ad-
ministered orally twice daily, is advised.[3] A dose of
mycophenolate mofetil 1.5g administered intrave-
nously or orally twice daily is recommended in adult
cardiac transplant recipients.[3] In paediatrics, an
oral dose of mycophenolate mofetil suspension 600
mg/m2 administered twice daily (up to a maximum
daily dose of 2g or 10mL) is recommended. Chil-
dren with a body surface area of 1.25–1.5m2 may be
given mycophenolate mofetil 750mg capsules twice
daily (1.5g daily dose). Children with a body surface
area >1.5m2 may be given mycophenolate mofetil
capsules or tablets 1g twice daily (2g daily dose).[3]
Mycophenolate mofetil oral suspension can be ad-
ministered via a nasogastric tube if necessary. Intra-
venous mycophenolate mofetil therapy should be
administered over at least 2 hours in adults, and
started within 24 hours following transplantation. It
may be continued for 14 days, but patients should be
converted to oral treatment as soon as it is tolera-
ble.[3] EC mycophenolate sodium tablets should not
be crushed, chewed or cut prior to ingestion, but
swallowed whole in order to maintain the integrity
of their enteric coating.[7]
Current manufacturer dosing guidelines for
mycophenolate mofetil in adult kidney transplant
recipients are largely based on results from three
randomised, double-blind, multicentre phase III tri-
als.[4-6,11] In these investigations, no further reduc-
tion in the incidence of acute rejection was observed
in patients who received a daily dose of mycopheno-
late mofetil 2g, compared with a daily dose of 3g,
from the time of transplant onwards. Subjects in all
three trials received ciclosporin co-therapy.
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
3. Clinical Pharmacokinetics
3.1 Absorption
Following oral administration, mycophenolate
mofetil and EC mycophenolate sodium are exten-
sively hydrolysed to MPA by esterases in the stom-
ach, small intestine, blood, liver and tissues.[12] In
two studies, one involving healthy volunteers and
the other heart transplant recipients, mycophenolate
mofetil plasma concentrations were below the limit
of assay detection (<0.4 mg/L and <0.02 mg/L,
respectively) at all times following an oral dose of
mycophenolate mofetil 1.5g.[13,14] Similarly, follow-
ing cessation of an intravenous infusion, mycophe-
nolate mofetil rapidly disappears from the plasma,
usually with no detectable concentration after 10–30
minutes.[13,14] A slower hydrolysis rate (>30 min-
utes) was reported in two individuals in one
study.[14] According to manufacturer information
(not available for critique), absorption of mycophe-
nolate mofetil is extensive, with >90% of radio-
labelled 14C recovered from the urine after a single
oral dose of 14C-mycophenolate mofetil in four fast-
ing healthy males.[15] In vitro studies indicate that
the enteric coating of EC mycophenolate sodium
remains largely intact at pH 5.0, as in the stomach,
but the tablet is highly soluble in neutral pH condi-
tions, as in the intestine.[16] Absorption of MPA
following administration of EC mycophenolate so-
dium is approximately 93%, according to manufac-
turer information.[7]
3.2 Oral Bioavailability
In a randomised, cross-over study of 12 healthy
volunteers, the bioavailability of oral relative to
intravenous mycophenolate mofetil, based on the
MPA area under the concentration-time curve from
0 to 24 hours (AUC24), was 94%.[13] Volunteers
received single mycophenolate mofetil 1.5g doses.
Oral and intravenous formulations of mycopheno-
late mofetil were also reported to be nearly
equivalent with regard to MPA exposure in a study
involving nine heart transplant recipients.[14] The
MPA AUC from 0 to 12 hours (AUC12) following
3-hour intravenous administration (mycophenolate
mofetil 1.5g twice daily) on days 3 and 5 post-
transplant was compared with MPA AUC12 follow-
© 2007 Adis Data Information BV. All rights reserved.
17
ing oral administration (mycophenolate mofetil 1.5g
twice daily) on days 6 and 10, with an average MPA
oral bioavailability of 95%. In contrast, a lower
mean oral bioavailability of 80.7% (90% CI 74.0,
88.8) was reported in one investigation in 31 renal
transplant recipients,[17] similar to a case report in-
volving another renal transplant recipient.[18] It is
possible that poor postoperative absorption or gas-
trointestinal tract metabolism, presumably via
glucuronidation, may play a role in the initial dispo-
sition of MPA in some transplant recipients. The
absolute bioavailability of MPA following EC
mycophenolate sodium administration in stable re-
nal transplant patients on ciclosporin-based immu-
nosuppression has been reported by the manufactur-
er to be approximately 72%.[7]
3.3 Distribution
In whole blood, 99.99% of MPA is found in the
plasma fraction with only 0.01% in cellular ele-
ments, supporting the rationale for quantitation of
MPA concentrations in plasma or serum.[19,20] MPA
binds extensively to serum albumin in the order of
97–99% in patients with normal renal and liver
function.[19,21-23] It does not bind significantly to
α1-acid glycoprotein.[19,24] Binding of MPA to se-
rum albumin is independent of MPA concentration
over a wide measurement range.[19] 7-O-MPA-
glucuronide (MPAG), the main metabolite of MPA,
also displays high serum albumin binding (approxi-
mately 82% in stable patients).[15] Only free (un-
bound) MPA is capable of inhibiting IMPDH in
vitro.[24]
The binding of MPA to plasma proteins is influ-
enced by the availability of serum albumin binding
sites and competition for these sites by MPAG and
urea. Significant renal dysfunction, liver disease and
hypoalbuminaemia can alter MPA and MPAG se-
rum albumin binding, changing the fraction of free
MPA available.[22,25-28] Interpretation of the total
MPA concentration can be difficult in clinical situa-
tions in which protein binding might be altered, as
changes in total concentration of MPA may not be
associated with parallel changes in free concentra-
tion.[29]
As mainly free drug is available for metabolism
and excretion, apparent oral clearance of total MPA
is likely to increase in proportion to increased free
Clin Pharmacokinet 2007; 46 (1)
18
(unbound) fraction.[22,30] While the total MPA con-
centration appears to be reduced as a result of in-
creased apparent drug clearance, the net result may
be little change in the absolute free concentration of
MPA. The idea that MPA clearance increases with
increased free fraction of the drug is supported by
investigations using an isolated re-circulating rat
liver perfusion system.[31] Using this system, MPA
free fraction was varied by changing the concentra-
tion of the binding protein in the perfusate.[31] A
4-fold decrease in MPA binding was accompanied
by a 5.3-fold increase in MPA clearance.[31]
The potential for drug-drug displacement from
plasma proteins has also been investigated in vi-
tro.[19] The binding of MPA was unaltered by nor-
mal therapeutic plasma concentrations of warfarin,
digoxin, phenytoin, ciclosporin, tacrolimus and
prednisone.[19] MPA free fraction showed a 6- to
8-fold progressive rise with an increase in sodium
salicylate concentration from 10 mg/L to 500 mg/
L.[19] MPA concentrations as high as 100 mg/L
(which are usually not achieved in vivo) had little
effect on the binding of warfarin, digoxin or propra-
nolol, but caused small decreases in the binding of
theophylline and phenytoin.[19] In 42 renal transplant
recipients, no significant difference could be found
in MPA free fraction between patients treated with
ciclosporin and those treated with tacrolimus.[32]
3.4 Metabolism
Uridine diphosphate glucuronosyltransferases
(UGTs) metabolise MPA via glucuronidation in the
gastrointestinal tract, liver and kidney.[33,34] MPAG,
the main metabolite, is a phenolic glucuronide,
which has no pharmacological activity with respect
to inhibition of IMPDH.[35] MPAG is usually pre-
sent in plasma at approximately 20- to 100-fold
higher concentrations than MPA. At least two other
minor metabolites are formed, a 7-O-glucoside and
an acyl-glucuronide (AcMPAG).[35-38] The 7-O-glu-
coside has no inhibitory effect on IMPDH, while
AcMPAG appears to inhibit IMPDH in vitro in a
concentration-dependent manner and at a pharmaco-
logical potency comparable to MPA.[35,36]
Acyl glucuronides, in general, are reactive elec-
trophilic metabolites capable of direct tissue damage
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
as a result of covalent binding to proteins, lipids and
nucleic acids.[39] AcMPAG may contribute to hyper-
sensitivity, drug toxicity and immune response in
patients receiving mycophenolate therapy.[39]
AcMPAG has shown a potential to induce cytokine
release and cytokine messenger RNA expression in
human mononuclear leukocytes.[40] High AcMPAG
concentrations may be associated with mycopheno-
late-related gastrointestinal adverse effects, al-
though this hypothesis has yet to be tested.[41,42]
UGT1A9 and 2B7 are believed to be the major
isoforms involved in MPA glucuronidation, possi-
bly because of their high hepatic and renal expres-
sion.[33] According to in vitro experimentation,
UGT1A9 is responsible for 55%, 75% and 50% of
MPAG production by the liver, kidney and intestinal
mucosa, respectively.[33] MPAG is also formed by
UGT1A7, 1A8 and 1A10, which are expressed in
the kidney and gastrointestinal tract.[33] UGT2B7 is
the only isoform reported to produce AcMPAG in
significant amounts.[33,43,44] Recently, a minor phase
I metabolite of MPA was detected and identified as
6-O-desmethyl-MPA (DM-MPA).[45] Cytochrome
P450 3A isoforms are believed to be involved in at
least 50% production of DM-MPA.[45]
3.5 Excretion
Following oral administration of radiolabelled
mycophenolate mofetil to four healthy, fasting male
volunteers, 93% of radioactivity was recovered in
the urine, approximately 87% as MPAG, while 6%
was recovered in the faeces.[15] Small amounts of
MPA (mean 0.6%; range 0–1.4% of the adminis-
tered dose) and AcMPAG (mean 0.3%; range
0–1.1% of the administered dose) were also de-
tected.[15] MPAG and AcMPAG are believed to be
mainly excreted into the urine via active tubular
secretion, possibly involving multi-drug resistance
protein 2 (MRP-2) mediated transport, although
more research is required in this area.[15,46] Excretion
into the bile of MPAG formed in the liver also
appears to involve MRP-2.[47,48] According to manu-
facturer information, approximately 3% of un-
changed MPA was detected in the urine following
administration of EC mycophenolate sodium to sta-
ble renal transplant patients.[7]
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
3.6 Enterohepatic Recirculation
MPAG excreted into the bile may be deconjugat-
ed back to MPA and reabsorbed in the colon. Con-
version is thought to occur through the action of
glucuronidase shed by gastrointestinal tract bacte-
ria.[13,49] It has been estimated that, on average,
enterohepatic recycling contributes approximately
40% (range 10–60%) to MPA exposure.[21] Biliary
excretion of MPA/MPAG and subsequent distal ab-
sorption and reabsorption are likely to require sever-
al transport mechanisms including organic anion
transporting polypeptides, MRP-2 and UGT.[46]
4. Pharmacokinetic Parameter Studies
Many pharmacokinetic studies have character-
ised the concentration-time profile of MPA and its
metabolites in different transplant groups. The ma-
jority have involved mycophenolate mofetil rather
than EC mycophenolate sodium formulations. The
pharmacokinetic parameters reported most often are
the AUC, maximum plasma drug concentration
(Cmax), time to reach Cmax (tmax), and minimum
plasma drug concentration (Ctrough). Tables I, II and
III summarise the pharmacokinetic parameters for
MPA, MPAG and free MPA, respectively, in differ-
ent transplant groups following multiple mycophe-
nolate dosing. Information on dosage, study period
post-transplant, immunosuppressant co-therapy and
the assay used for drug measurement is provided.
The pharmacokinetics of MPA following admin-
istration of mycophenolate mofetil and EC
mycophenolate sodium are linear over the normal
dosing range.[8,86] MPA AUC has been reported to
be independent of the intravenous infusion time.[17]
Following mycophenolate mofetil administration,
MPA tmax usually occurs 1–2 hours post-dose. EC
mycophenolate sodium shows a median lag time
(tlag) in the rise of the MPA concentration from 0.25
to 1.25 hours.[7,87] tmax usually occurs 1.5–2.75
hours postdose.[7,65,88] tlag differences between EC
mycophenolate sodium and mycophenolate mofetil
dosing are statistically significant.[16] Administra-
tion of EC mycophenolate sodium 720mg results in
similar MPA Cmax and AUC values as mycopheno-
late mofetil 1g.[65,87] At this dosing level, the two
compounds are considered bioequivalent.[16,87] Sim-
ilar exposure to MPAG and AcMPAG has been
© 2007 Adis Data Information BV. All rights reserved.
19
reported from mycophenolate mofetil and EC
mycophenolate sodium treatment.[16,64] No differ-
ence in IMPDH inhibition was observed in 14 kid-
ney transplant recipients who received EC
mycophenolate sodium 720mg twice daily or
mycophenolate mofetil 1g twice daily.[65] Estimates
of the mean elimination half-life (t1/2) of MPA range
from 9 to 17 hours.[16,88,89] The concentration-time
profile of MPA often shows two peaks. The second,
seen at around 4–12 hours, is attributed to enter-
ohepatic recycling.[21,90,91] A significant portion of
between-occasion variability in MPA trough con-
centrations (Ctrough) may be due to day-to-day fluc-
tuations in enterohepatic recirculation.[90]
The pharmacokinetics of MPAG are summarised
in table II. MPAG Cmax occurs at a mean of around
1–4 hours (range 0.25–12 hours). In a longitudinal
study of 33 renal transplant patients receiving
tacrolimus co-therapy, high initial MPAG AUC and
Ctrough values decreased with improving renal func-
tion and reached stable values after 6 weeks.[61] A
clear (inverse) correlation between MPAG Ctrough,
MPAG AUC and glomerular filtration rate (GFR)
was evident, as was a correlation between MPAG
AUC and free MPA AUC. AcMPAG constituted a
mean of 9.7%, 6.5% and 7.3% of the MPA AUC at 7
days, 3 months and 12 months post-transplant, re-
spectively.
Pharmacokinetic values for free MPA are provid-
ed in table III. In several studies, MPA free fraction
appears to decrease with time post-transplant.[68,71,76]
MPA free fraction AUC fell from 2.12% in the first
week to 0.94% at 3 months and 0.86% at 12 months
post-transplant in a longitudinal study of 33 renal
transplant recipients.[61] The mean free MPA AUC
showed a secondary concentration peak at 6 hours
postdose, with large between-patient variability, in-
dicative of highly variable enterohepatic recycling.
Free MPA AUC was inversely correlated with GFR.
MPA free fraction was positively correlated with
MPAG AUC.
As is evident in tables I, II and III, mycopheno-
late displays complex and somewhat erratic
pharmacokinetics with large between- and within-
subject variability.[15,22,90,92,93] The dose-normalised
MPA AUC12 (to mycophenolate mofetil 1g twice
daily) has been reported to vary more than 10-fold
(range 7.5–94.7 mg • hr/L) during the first 2 weeks
Clin Pharmacokinet 2007; 46 (1)
 20
Table I. Pharmacokinetic parameters for mycophenolic acid in different transplant groups following multiple dosing
No. of Dose Time post- tmax (h)b Cmax (mg/L)b Ctrough (mg/L)b AUC12 (mg • h/L)b r2 between Reference
patients (twice daily)a transplant Ctrough and
AUC12
Adult kidney
18c,d 1g MMF 3wk 1.8 ± 1.8 9.6 ± 5.6 1.8 ± 1.4 41.0 ± 19.4 0.27–0.41 50
24c,d 1g MMF ≤30d 10.3 ± 4.9 2.0 ± 1.0 46.0 ± 18.4 0.44–0.52 51
24c,d 1g MMF ≥3mo 17.1 ± 7.2 1.7 ± 0.8 49.3 ± 11.1
22c,e 1g MMF 12d 1.0 ± 0.4 15.8 ± 12.5 33.9 ± 9.0 52
45c,e 0.5–2g/d MMF 46mo (range 4–169) 1.4 (0.4–5.6)f 34.3 (14.1–65.4)f 0.07 53
1c,d 1g MMF ~1y 1 21.7 2.1 65.6 18
0.5g (IV) MMF ~1y 1 28.5 0.7 56.2
19g,e 0.5g MMF 2wk 25 54
19g,e 1g MMF 2wk 40

© 2007 Adis Data Information BV. All rights reserved.

6c,e 1g MMF 1wk 1.7 ± 1.3 12.3 ± 7.9 0.8 ± 0.2 27.7 ± 4.5 0.12 55
1mo 1.9 ± 1.2 13.3 ± 7.0 1.0 ± 0.2 34.1 ± 4.2
3mo 2.1 ± 1.5 16.2 ± 11.8 1.2 ± 0.8 45.0 ± 11.8
10c,e 0.75g MMF 2wk 1.1 ± 1.1 8.7 ± 4.7 18.5 ± 4.3 0.56 56
8c,d 1g MMF >1y 1.7 ± 0.7 48.5 ± 14.7 0.48 57
11d,h 1g MMF >1y 5.7 ± 3.5 78.4 ± 28.8
6d,h 0.5g MMF >1y 2.5 ± 0.9 40.0 ± 8.8
31c,e 1g MMF 6d 1.3 ± 1.1 10.7 ± 4.8 32.9 ± 15.0 17
31c,e 1g (IV) MMF 5d 1.6 ± 0.5 12.0 ± 3.8 40.8 ± 11.4
10c,e 1g MMF 38.5 ± 44.8mo 1.4 ± 1.0 12.0 ± 5.7 2.1 ± 1.2 49.8 ± 24.8 0.38–0.66 58
7c,e 0.75g MMF 38.5 ± 44.8mo 1.6 ± 1.2 14.1 ± 11.7 1.4 ± 0.6 41.7 ± 13.2
10c,e 0.5g MMF 38.5 ± 44.8mo 0.9 ± 0.6 16.2 ± 12.5 1.8 ± 0.7 42.9 ± 17.9
16c,d,e 1g MMF >10wk 0.8 ± 0.5 36.8 ± 18.0 76.6 ± 24.4 59
25c,e 1g MMF <3mo 1.9 ± 1.3 44.8 ± 12.8 0.38 60
1g MMF >3mo 2.3 ± 0.9 61.3 ± 20.4
33g,e 1g MMF 1wk 0.78 (0.33–12)f 10.3 (4.6–26.5)f 1.5 (0.1–5.0)f 43.8 (16.7–71.2)f 0.33 61
1g MMF 6wk 2.2 (0.2–7.1)f 59.9 (18.6–211)f
1g MMF 3mo 2.4 (0.3–5.7)f 60 (24–111)f
1g MMF 12mo 2.0 (0.4–8.0)f 58.8 (27–111)f
21g,e 33.1 ± 9.4 mg/kg MMF 28d 3.2 ± 2.0 11.0 ± 7.6 53.0 ± 12.5 62
10c,e 1g MMF 2d 2.2 ± 0.5 11.1 ± 1.3 42.3 ± 2.3 0.37 63
1g MMF 5d 1.9 ± 0.4 11.9 ± 2.5 35.7 ± 3.2
1g MMF 28d 1.6 ± 0.4 14.9 ± 1.9 37.5 ± 2.7

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Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
 Table I. Contd
No. of Dose Time post- tmax (h)b Cmax (mg/L)b Ctrough (mg/L)b AUC12 (mg • h/L)b r2 between Reference
patients (twice daily)a transplant Ctrough and
AUC12
10c,e 1g MMF 1wk 1.9 ± 0.7 7.0 ± 1.3 0.7 ± 0.1 22.1 ± 1.8 0.41–0.56 22
3wk 1.5 ± 0.2 10.2 ± 1.9 1.2 ± 0.4 30.9 ± 4.6
0.5g MMF 6wk 0.8 ± 0.5 15.2 ± 7.4 2.6 ± 1.9 52.0 ± 26.1
0.5g MMF 3mo 1.0 ± 0.6 14.4 ± 6.8 2.8 ± 1.4 36.7 ± 21.2
0.5g MMF 12mo 0.8 ± 0.5 17.4 ± 10.2 3.6 ± 3.2 43.8 ± 25.5
34d,g 1g MMF 7d 1.1 ± 0.6 14.6 ± 6.7 2.5 ± 1.3 55.4 ± 23.2
1g MMF 6wk 0.7 ± 0.3 20.8 ± 10.9 3.6 ± 1.8 77.4 ± 29.5
1g MMF 3mo 0.8 ± 0.3 24.2 ± 12.8 3.8 ± 1.7 61.3 ± 29.5
1g MMF 12mo 0.9 ± 0.3 22.2 ± 11.0 3.9 ± 1.9 53.8 ± 24.8
40c,e 1g MMF >6mo 1.0 (0.5–3.0)f 25.5 1.7 61.4 64

© 2007 Adis Data Information BV. All rights reserved.

0.75g EC-MPS >6mo 2.5 (1.5–8.0)f 33.4 1.7 74.7
14 1g MMF 0.9 ± 0.4 20.2 ± 8.6 1.6 ± 0.7 55.7 ± 9.9 65
0.75g EC-MPS 2.3 ± 1.4 19.2 ± 8.9 3.7 ± 2.3 56.0 ± 15.3
10c 0.72g EC-MPS 2.0 (1.5–3.0)f 37.0 ± 13.3 67.9 ± 20.3 7
36c 0.72g EC-MPS 2.5 (1.5–8.0)f 31.2 ± 18.1 71.2 ± 26.3 7
12c 0.72g EC-MPS 2wk 1.8 (1.0–5.3)f 15.0 ± 10.7 28.6 ± 11.5 7
0.72g EC-MPS 3mo 2.0 (0.5–2.5)f 26.2 ± 12.7 52.3 ± 17.4
PK and PD of Mycophenolate in Solid Organ Transplantation

0.72g EC-MPS 6mo 2.0 (0–3.0)f 24.1 ± 9.6 57.2 ± 15.3

18c 0.72g EC-MPS 1.5 (0–6.0)f 18.9 ± 7.9 57.4 ± 15.0 7
12c,e 0.72g EC-MPS 2wk 3.1 ± 0.8 74.3 ± 44.3 66
27e 1g MMF 2wk 11.6 23.3i 67
1g MMF 3mo 17.9 39.1i
1g MMF 6mo 18.6 37.2i
24e 0.75g EC-MPS 2wk 13.9 29.1i
0.75g EC-MPS 3mo 24.6 50.7i
0.75g EC-MPS 6mo 23.0 55.7i
Adult liver
10e,g 0.5–1g MMF ≤1wk 1.8 ± 1.2 9.1 ± 7.2 50.8 ± 42.1 0.6 68
0.5–1g MMF >1wk, ≤2wk 1.8 ± 1.4 11.6 ± 6.7 60.3 ± 38.5
0.5–1g MMF ≥3wk, ≤6wk 1.3 ± 0.7 36.7 ± 15.6 118.0 ± 57.6
8e,g 1g MMF ≤30d 1.8 ± 1.6 10.6 ± 7.5 1.1 ± 1.4 40.0 ± 30.9 0.57 69
Adult lung
7c,e 35.5 ± 14.1 mg/kg/d MMF 4.4y (range 0.3–11.5) 1.2 ± 0.4 17.4 ± 7.7 3.1 ± 1.4 45.8 ± 18.4 23

Continued next page

Clin Pharmacokinet 2007; 46 (1)

21
 22
Table I. Contd
No. of Dose Time post- tmax (h)b Cmax (mg/L)b Ctrough (mg/L)b AUC12 (mg • h/L)b r2 between Reference
patients (twice daily)a transplant Ctrough and
AUC12
Adult heart
9c,e 1.5g MMF 6d 2.0 (0.3–6.0)f 6.0 (4.4–10.5)f 0.6 (0.2–1.1)f 29.7 (22.3–37.6)f 14
1.5g MMF 10d 1.3 (0.7–1.3)f 9.0 (3.6–10.8)f 1.0 (0.5–1.4)f 33.8 (26.6–40.3)f
1.5g (IV) MMF 3d 2.0 (1.0–3.0)f 10.2 (7.6–16.7)f 0.7 (0.2–1.4)f 34.2 (22.3–52.1)f
1.5g (IV) MMF 5d 2.0 (2.0–3.0)f 9.8 (6.1–11.2)f 1.0 (0.3–1.1)f 33.8 (23.7–43.1)f
38c,e 1.09 ± 0.36g MMF 310 ± 278d 1.2 ± 0.6 44.5 ± 16.1 0.16 70
Adult heart/lung
7c,e 2429 ± 535 mg/d MMF 15 ± 13d 4.0 ± 4.2 9.3 ± 4.2 3.8 ± 4.0 30.1 ± 18.2 71
2357 ± 476 mg/d MMF 56 ± 33d 0.7 ± 0.4 8.3 ± 4.2 2.2 ± 2.6 19.8 ± 11.0
2214 ± 393 mg/d MMF 125 ± 73d 1.7 ± 1.3 10.3 ± 7.9 2.2 ± 2.3 36.8 ± 29.7

© 2007 Adis Data Information BV. All rights reserved.

Paediatric kidney
8c,e 495 ± 143 mg/m2 MMF 55mo (range 7.5–124) 1.4 ± 0.5 16.2 ± 7.3 4.7 ± 1.3 57.0 ± 15.3 72
16j 600 mg/m2 MMF 1wk 27.4 ± 9.4 73
9j 600 mg/m2 MMF 3mo 52.0 ± 19.0
4j 600 mg/m2 MMF 9mo 66.7 ± 15.1
17k 600 mg/m2 MMF 1wk 31.5 ± 10.5
9k 600 mg/m2 MMF 3mo 51.6 ± 17.3
4k 600 mg/m2 MMF 9mo 62.1 ± 18.3
21l 600 mg/m2 MMF 1wk 26.2 ± 9.6
15l 600 mg/m2 MMF 3mo 43.1 ± 17.0
4l 600 mg/m2 MMF 9mo 53.6 ± 18.8
18c,e 600 mg/m2 MMF 1wk 1.6 ± 0.4 12.5 ± 1.5 1.5 ± 0.3 36.5 ± 2.9 0.32–0.52 22
600 mg/m2 MMF 3wk 1.0 ± 0.1 19.6 ± 2.5 1.1 ± 0.2 34.0 ± 3.1
17c,e 600 mg/m2 MMF 1wk 0.7 (0.3–6.0)f 12.3 (5.0–28.6)f 1.3 (0.3–5.2)f 41.0 (19.2–55.6)f 74
600 mg/m2 MMF 3wk 0.7 (0.3–2.0)f 18.7 (5.3–45.7)f 0.7 (0.2–2.9)f 32.4 (13.9–57.0)f
600 mg/m2 MMF 3mo 1.2 (0.3–4.0)f 25.6 (5.1–53.5)f 1.6 (1.0–2.4)f 65.1 (32.6–114)f
600 mg/m2 MMF 6mo 1.2 (0.3–2.0)f 25.1 (15.5–43.3)f 1.8 (0.4–3.6)f 64.3 (21.3–85.5)f
7d,g 496 ± 282 mg/m2/d MMF 14d (10–18) 1.0 (0.5–2.0)f 14.5 ± 4.7 59.9 ± 10.5 0.69 75
17e 600 mg/m2 MMF 3wk 32.4 (13.9–57.0)f 76
3mo 65.1 (32.6–114)f
23c,d 1043 ± 319 mg/m2/d MMF 2mo–10.1y 1.0 (0.5–3.0)f 15.2 ± 6.2 3.9 ± 2.7 60.7 ± 29.8 77
40 600 mg/m2 MMFc,e 1wk 10.2 (3.0–32.1)f 1.1 (0.2–2.7)f 34.2 (11.8–62.8)f 78
600 mg/m2 MMFc,d 1wk 11.9 (8.7–20.2)f 1.3 (0.3–4.4)f 39.1 (15.3–78.9)f

Continued next page

Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
 Table I. Contd
No. of Dose Time post- tmax (h)b Cmax (mg/L)b Ctrough (mg/L)b AUC12 (mg • h/L)b r2 between Reference
patients (twice daily)a transplant Ctrough and
AUC12
600 mg/m2 MMFc,e 3wk 14.2 (4.5–45.7)f 1.0 (0.2–2.5)f 32.0 (12.8–57.0)f
600 mg/m2 MMFc,d 3wk 14.8 (4.8–50.1)f 1.4 (0.4–2.7)f 39.5 (15.4–67.8)f
34c,d 716 ± 254 mg/m2 MMF d6 0.8 ± 0.6 23.3 ± 10.8 0.42 79
680 ± 239 mg/m2 MMF d180 1.9 ± 1.1 40.0 ± 11.6
54c,e 600 mg/m2 MMF 1wk 10.0 (1.5–42.3)f 1.1 (0.1–4.1)f 36.0 (3.1–95.0)f 0.41 80
600 mg/m2 MMF 3wk 15.3 (3.5–45.7)f 1.0 (0.1–15.6)f 33.6 (12.8–89.1)f
600 mg/m2 MMF 3mo 24.9 (7.2–53.5)f 2.3 (0.4–11.2)f 63.5 (28.6–139)f
600 mg/m2 MMF 6mo 26.0 (9.4–52.5)f 2.9 (0.2–12.6)f 65.7 (21.3–117)f
8c,e 495 ± 143mg/m2 MMF >1y 1.4 ± 0.5 16.2 ± 7.3 57.0 ± 15.3 81

© 2007 Adis Data Information BV. All rights reserved.

16c,e 600 mg/m2 MMF 1–3wk 0.7 (0.3–2.0)f 13.5 (2.3–24.8)f 1.5 (0.4–3.7)f 27.5 (12.9–93.2)f 82
22c,e 600 mg/m2 MMF 3–12mo 1.3 (0.3–2.0)f 26.6 (12.1–47.2)f 2.7 (0.2–7.4)f 60.7 (37.0–117.0)f
17c,e,m 600 mg/m2 MMF 1wk 1.6 ± 2.9 13.2 ± 7.2 27.4 ± 9.5 83
15c,e,m 600 mg/m2 MMF 3mo 1.0 ± 0.5 22.7 ± 10.1 49.7 ± 18.2
12c,e,m 600 mg/m2 MMF 9mo 0.9 ± 0.5 30.4 ± 9.2 60.9 ± 10.7
16c,e,k 600 mg/m2 MMF 1wk 0.9 ± 0.5 13.1 ± 6.3 33.2 ± 12.1
14c,e,k 600 mg/m2 MMF 3mo 1.2 ± 0.5 27.8 ± 14.3 61.9 ± 19.6
PK and PD of Mycophenolate in Solid Organ Transplantation

11c,e,k 600 mg/m2 MMF 9mo 1.1 ± 0.5 29.2 ± 12.6 66.8 ± 21.2
21c,e,l 600 mg/m2 MMF 1wk 1.2 ± 0.8 11.7 ± 10.7 26.3 ± 9.1
17c,e,l 600 mg/m2 MMF 3mo 1.0 ± 0.5 17.9 ± 9.6 53.6 ± 20.2
14c,e,l 600 mg/m2 MMF 9mo 1.1 ± 0.5 18.1 ± 7.3 56.7 ± 14.0
a Oral unless specified otherwise.
b Values are expressed as mean ± SD unless specified otherwise.
c Ciclosporin co-therapy.
d Enzyme immunoassay.
e Liquid chromatography.
f Median (range).
g Tacrolimus co-therapy.
h Without calcineurin inhibitors.
i AUC24
j 0.3mo to <6y of age.
k ≥6y to <12y of age.
l ≥12y to 18y of age.
m <6y of age.
AUC12 = area under the concentration-time curve from 0 to 12 hours; AUC24 = AUC from 0 to 24 hours; Cmax = maximum drug concentration; Ctrough = trough concentrations; EP-
MCS = enteric-coated mycophenolate sodium; IV = intravenous; MMF = mycophenolate mofetil; tmax = time to reach Cmax.

Clin Pharmacokinet 2007; 46 (1)

23
 Table II. Pharmacokinetic parameters for mycophenolic acid glucuronide (MPAG) in different transplant groups following multiple dosing 24
No. of Dose Time post- tmax (h)b Cmax (mg/L)b Ctrough AUC12 MPAG Serum creatinine Reference
patients (twice daily)a transplant (mg/L)b (mg • h/L)b AUC : MPA (mg/dL)b
AUCb
Adult kidney
40c,d,e 1g MMF 28d 3.8 ± 2.1 83.7 ± 33.9 554 ± 262f 1.8 84
21c,d 1g MMF 28d 3.8 ± 2.3 98.9 ± 30.3 673 ± 210f 1.5
40c,d,e 1g MMF 56d 3.9 ± 2.2 76.7 ± 22.5 495 ± 160f 1.4
21c,d 1g MMF 56d 3.7 ± 2.4 90.8 ± 31.5 609 ± 221f 1.6
31c,d 1g MMF 6d 3.6 ± 2.7 80.2 ± 27.5 746 ± 302 17
31c,d 1g (IV) MMF 5d 3.4 ± 2.0 74.6 ± 27.3 720 ± 316
33d,g 1g MMF 1wk 2.0 (0.8–12)h 119 (45–516)h 84 (14–428)h 1153 (333–6123)h 2.8 ± 2.2 61
1g MMF 6wk 53 (3–136)h 908 (239–3904)h 1.5 ± 0.4
1g MMF 3mo 56 (20–92)h 778 (362–1882)h 1.5 ± 0.4

© 2007 Adis Data Information BV. All rights reserved.

1g MMF 12mo 44 (13–157)h 739 (349–1615)h 1.5 ± 0.6
10 1g MMF d2 1983 ± 209 0.241 ± 0.048 mmol/L 63
1g MMF d5 1732 ± 272 0.157 ± 0.019 mmol/L
1g MMF d28 1572 ± 127 0.133 ± 0.025 mmol/L
10c,d 1g MMF 1wk 3.9 ± 1.2 215 ± 26 163 ± 25 2095 ± 259 27 ± 8 mL/min/1.73m2i 22
1g MMF 3wk 3.3 ± 0.8 193 ± 22 137 ± 21 1901 ± 212 50 ± 7 mL/min/1.73m2i
40c,d 1g MMF >6mo 2.5 (0.5–6.0)h 184.7 64 1413 64
0.72g EC-MPS >6mo 4 (0.25–8.0)h 223.7 84 1724
12c,d 0.72g EC-MPS 2wk 373 ± 111 66

Adult liver
10d,g 0.5–1g MMF ≤1wk 4.7 ± 2.2 14.9 ± 97.5 843 ± 630 25.5 ± 21.2 0.5–1.3 68
0.5–1g MMF >1wk, 3.7 ± 1.9 113.1 ± 78.9 737 ± 357 16.8 ± 13.2 0.6–1.5
≤2wk
0.5–1g MMF ≥3wk, 3.4 ± 1.9 139.5 ± 130.9 751 ± 420 8.0 ± 3.3 0.7–1.5
≤6wk
8d,g 1g MMF ≤30d 115.3 ± 45.0 1049 ± 558 63.7 ± 83.6 2.1 ± 1.6 69

Adult heart
9c,d 1.5g MMF 6d 4.0 (0.7–8.0)h 96 (51–111)h 56 (26–82)h 959 (471–1216)h 14
1.5g MMF 10d 2.5 (1.3–4.0)h 108 (59–179)h 79 (28–122)h 1032 (573–1498)h 1.2 ± 0.3
1.5g (IV) MMF 3d 3.0 (2.5–3.5)h 110 (65–187)h 69 (34–153)h 1030 (537–2049)h 1.4 ± 0.5
1.5g (IV) MMF 5d 3.2 (3.0–4.0)h 109 (51–166)h 63 (34–135)h 881 (456–1584)h 1.2 ± 0.4

Continued next page

Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
 Table II. Contd
No. of Dose Time post- tmax (h)b Cmax (mg/L)b Ctrough AUC12 MPAG Serum creatinine Reference
patients (twice daily)a transplant (mg/L)b (mg • h/L)b AUC : MPA (mg/dL)b
AUCb
Paediatric kidney
8c,d 495 ± 143 mg/m2 MMF 55mo 3.1 ± 1.2 164 ± 76 1515 ± 722 25.6 ± 8.7 0.164 ± 0.043 mmol/L 72
(range
7.5–124)
18c,d 600 mg/m2 MMF 1wk 3.1 ± 0.5 179 ± 29 112 ± 28 1654 ± 337 57 ± 9 mL/min/1.73m2i 22
600 mg/m2 MMF 3wk 2.1 ± 0.3 129 ± 9 53 ± 7 987 ± 93 88 ± 7 mL/min/1.73m2i
17c,d 600 mg/m2 MMF 1wk 2.0 (1.3–8.0)h 147 (84–511)h 62 (9–452)h 1319 (436–5532)h 59 ± 10 mL/min/1.73m2i 74
600 mg/m2 MMF 3wk 2.0 (1.3–4.0)h 131 (73–248)h 46 (7–180)h 987 (410–2242)h 89 ± 8 mL/min/1.73m2i
600 mg/m2 MMF 3mo 2.0 (1.3–6.0)h 148 (58–208)h 35 (10–94)h 953 (434–1685)h 94 ± 5 mL/min/1.73m2i

© 2007 Adis Data Information BV. All rights reserved.

600 mg/m2 MMF 6mo 2.0 (1.3–6.0)h 111 (11–221)h 28 (8–104)h 787 (459–1936)h 90 ± 6 mL/min/1.73m2i
7g,j 496 ± 282 mg/m2/d MMF 14d (range 1.5 (1.0–3.0)h 139 ± 63 1137 ± 612 75
10–18)
16c,d 600 mg/m2 MMF 1–3wk 2.0 (1.3–4.0)h 69 (39–134)h 34 (13–91)h 593 (335–1366)h 79.2 mL/min/1.73m2i 82
c,d h h h h
22 600 mg/m2 MMF 3–12mo 2.0 (1.3–4.0) 109 (49–214) 51 (13–128) 894 (327–1985) 81.7 mL/min/1.73m2i
PK and PD of Mycophenolate in Solid Organ Transplantation

Paediatric liver
10c,d 500mg (250–1000) MMF >6mo 2.0 (1.5–4.0)h 44 (27–78)h 17 (7–54)h 229k (136–486)h 85
g,d
11 250mg (65–500) MMF >6mo 2.0 (0.7–3.7)h 25 (7–60)h 6 (5–18)h 94k (59–280)h

a Oral unless specified otherwise.

b Values are expressed as mean ± SD unless specified otherwise.
c Ciclosporin co-therapy.
d Liquid chromatography.
e Daclizumab co-therapy.
f AUC8.
g Tacrolimus co-therapy.
h Median (range).
i Creatinine clearance.
j Enzyme immunoassay.
k AUC7.
AUC7 = area under the concentration-time curve from 0 to 7 hours; AUC8 = AUC from 0 to 8 hours; AUC12 = AUC from 0 to 12 hours; Cmax = maximum drug concentration; Ctrough
= trough concentrations; EP-MCS = enteric-coated mycophenolate sodium; IV = intravenous; MMF = mycophenolate mofetil; MPA = mycophenolic acid; tmax = time to reach Cmax.

Clin Pharmacokinet 2007; 46 (1)

25
 Table III. Pharmacokinetic parameters for free mycophenolic acid in different patient groups following multiple dosing 26
No. of Dose Time post- tmax (h)a Cmax (μg/L)a Ctrough (μg/L)a AUC12 Free fraction Reference
patients (twice daily) transplant (mg • h/L)a (%)a,b
Adult kidney
32c,d 1g MMF 5d 37 (13–74)e 1.2 ± 0.8f 5.0 (3.1–8.5)e 32
10d,g 1g MMF 5d 62 (44–76)e 1.1 ± 0.6f 4.2 (2.9–6.9)e
10c,d 0.75g MMF 2wk 1.6 ± 0.2 56
33d,g 1g MMF 1wk 0.8 (0.3–12)e 220 (60–410)e 30 (<10–120)e 0.9 ± 0.6 2.1 61
1g MMF 6wk
1g MMF 3mo 30 (<10–100)e 0.6 ± 0.3 1.3
1g MMF 12mo 20 (10–120)e 0.6 ± 0.3 1.7
10c,d 1g MMF 1wk 2.6 ± 0.8 210 ± 30 20 ± 10 0.8 ± 0.1 22
1g MMF 3wk 1.4 ± 0.2 210 ± 30 20 ±5 0.6 ± 0.1

Adult liver

© 2007 Adis Data Information BV. All rights reserved.

10d,g 0.5–1g MMF ≤1wk 4.3 ± 2.2 68
0.5–1g MMF >1wk, ≤2wk 2.9 ± 0.8
0.5–1g MMF ≥3wk, ≤6wk 1.9 ± 1.0
8d,g 1g MMF ≤30d 3.9 ± 1.6 69

Adult lung
7c,d 35.5 ± 14.1 mg/kg/d MMF 4.4y (range 0.3–11.5) 1.3 ± 0.5 2.9 ± 0.6 23

Adult heart
38c,d 1.09 ± 0.36g MMF 310 ± 278d 0.8 ± 0.3 1.9 ± 0.4 70
7c,d 2429 ± 535 mg/d MMF 15 ± 13d 2.2 ± 2.3 6.1 ± 2.8 71
2357 ± 476 mg/d MMF 56 ± 33d 1.0 ± 0.8 4.3 ± 2.4
2214 ± 393 mg/d MMF 125 ± 73d 1.5 ± 2.2 4.4 ± 3.0

Paediatric kidney
17d 600mg/m2 MMF 1–3wk 1.4 (0.6–5.1)e 76
600 mg/m2 MMF 3–6mo 0.9 (0.5–1.9)e
54c,d 600 mg/m2 MMF 1wk 170 (30–610)e 10 (<10–90)e 0.4 (0.1–1.6)e 80
600 mg/m2 MMF 3wk 200 (30–650)e 10 (<10–150)e 0.4 (0.1–1.2)e
600 mg/m2 MMF 3mo 230 (80–610)e 20 (<10–170)e 0.5 (0.2–1.4)e
600 mg/m2 MMF 6mo 210 (70–570)e 20 (<10–110)e 0.5 (0.2–1.3)e
18c,d 600 mg/m2 MMF 1wk 1.6 ± 0.4 230 ± 20 30 ± 10 0.7 ± 0.1 22
600 mg/m2 MMF 3wk 1.1 ± 0.2 300 ± 40 10 ±2 0.5 ± 0.1
17c,d 600 mg/m2 MMF 1wk 0.7 (0.3–6.0)e 230 (60–470)e 20 (<10–110)e 0.5 (0.2–2.3)e 1.3 (0.6–5.1)e 74
600 mg/m2 MMF 3wk 0.7 (0.3–2.0)e 200 (120–650)e 10 (<10–30)e 0.5 (0.1–1.2)e 1.4 (0.6–4.7)e

Continued next page

Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
PK and PD of Mycophenolate in Solid Organ Transplantation 27

AUC6 = area under the concentration-time curve from 0 to 6 hours; AUC12 = AUC from 0 to 12 hours; Ctrough = trough concentrations; Cmax = maximum drug concentration; MMF =
following kidney transplant surgery.[92] Studies in-
vestigating reasons for MPA pharmacokinetic varia-
Reference

bility are discussed in section 5. Example MPA

concentration-time profiles from three different
adult kidney transplant recipients (the patients were
part of study analysed by Shum et al.[90]) are dis-
0.9 (0.5–1.9)e

0.9 (0.5–3.3)e
Free fraction

played in figure 1. Each profile demonstrates a

different feature of MPA pharmacokinetics: (i) a
(%)a,b

single peak; (ii) a lag time in absorption; and (iii) a

secondary peak due to enterohepatic recirculation.
All patients received oral mycophenolate mofetil 1g
0.5 (0.3–0.9)e

0.5 (0.3–1.0)e

twice daily. Patients were <1 month post-renal

(mg • h/L)a

transplant and received concomitant ciclosporin and

AUC12

prednisone therapy.

5. Reasons for
Ctrough (μg/L)a

Pharmacokinetic Variability
10 (<10–30)e

10(<10–70)e

5.1 Renal Impairment

Significantly impaired renal function leads to

230 (90–620)e

230 (60–700)e

reduced renal excretion of MPAG, causing concen-

Cmax (μg/L)a

trations to become markedly elevated.[94] In patients

with a GFR <25 mL/min, MPAG accumulates 3- to
6-fold.[94] Accumulated MPAG competes with and
displaces MPA from protein binding sites.[19,28,74,95]
Uraemia also decreases MPA binding to albumin.[28]
0.7 (0.3–2.0)e

1.0 (0.3–4.0)e

Uremic sera without MPAG demonstrated a 2-fold

tmax (h)a

decrease in MPA albumin binding that was progres-

sively decreased further by the addition of graded
Values are expressed as mean ± SD unless specified otherwise.

amounts of MPAG.[28] Higher MPAG concentra-

tions and worsening uraemia lead to a progressive
increase in MPA free fraction.[28,74,95] MPA free
fraction is in the order of 1–2.5% in subjects with
Time post-
transplant

normal renal function, but increases to 7% or more

mycophenolate mofetil; tmax = time to reach Cmax.

in patients with impaired renal function.[25,28,74,95,96]

3mo

6mo

Caution should be used in interpreting total MPA

concentration in patients with severe renal impair-
ment.[25]

5.2 Hepatic Impairment

600 mg/m2 MMF

600 mg/m2 MMF

Liquid chromatography.
Ciclosporin co-therapy.

Tacrolimus co-therapy.
Percentage free/total.
(twice daily)

In a single-dose pharmacokinetic study of oral

mycophenolate mofetil in 18 patients with compen-
Median (range).
Dose

sated alcoholic cirrhosis, cirrhosis did not signifi-

Table III. Contd

cantly affect the pharmacokinetic profile of MPA or

AUC6.

MPAG compared with controls.[97] It was suggested

patients
No. of

that reduced hepatic glucuronidation of MPA may

be compensated by enhanced renal glucuronida-
a

g
c

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (1)
28 Staatz & Tett

a
over one dosing interval in eight liver transplant
12
recipients on concomitant tacrolimus and corticoste-
10 roid therapy.[98]
8

6
5.3 Food

4 MPA AUC12 following fatty food administration

2 was similar to that following overnight fasting in a
crossover study in which a single mycophenolate
0
mofetil 2g dose was given orally to ten rheumatoid
b arthritis patients.[99] However, MPA tmax was slight-
12
ly delayed, and Cmax was 25% lower, consistent
MPA concentration (mg/L)

10 with a delay in gastric emptying in the fed state.[99]

8 MPAG Cmax and AUC12 were higher in the fed
relative to the fasting state, suggesting that more
6
complex processes involving changes in
4 glucuronidation may be involved.[99] According to
2 manufacturer information, food (27g fat, 650 calo-
0
ries) had no effect on the extent of MPA absorption
when mycophenolate mofetil was administered at a
c
12
dose of 1.5g twice daily to renal transplant recipi-
ents.[3] However, MPA Cmax decreased by 40%,
10
leading to the recommendation that mycophenolate
8 mofetil be administered on an empty stomach early
6 after transplantation. In stable patients, mycopheno-
4
late mofetil may be administered with food if neces-
sary.[3] According to manufacturer information, a
2
high-fat meal (55g fat, 1000 calories) had no effect
0 on MPA AUC compared with the fasting state fol-
0 2 4 6 8 10 12
Time post-dose (h)
lowing administration of EC mycophenolate sodium
720mg.[7] However, food caused a 33% decrease in
Fig. 1. Mycophenolic acid (MPA) plasma concentration-time profile
with (a) a single peak, (b) a lag time, and (c) enterohepatic recircu- Cmax, a 3.5-hour delay in tlag (range –6 to 18 hours)
lation seen following oral mycophenolate mofetil administration. and a 5-hour delay in tmax (range, –9 to 20 hours) of
MPA. To reduce variability in MPA absorption be-
tion.[97] It should be noted, however, that healthy tween doses, it is recommended that EC mycophe-
control subjects in this investigation had approxi- nolate sodium be taken on an empty stomach.[7]
mately 50% lower MPA AUC compared with
healthy volunteers in other studies. According to 5.4 Dialysis
manufacturer recommendations, no mycophenolate In eight renal transplant recipients with delayed
mofetil dose adjustment is required for renal trans- graft function, haemodialysis did not lower MPA
plant patients with hepatic parenchymal disease.[3] plasma concentrations between input and output
To date, it is not known whether mycophenolate dialysis coils during patients’ second (n = 8) and
dosage should be altered in patients with hepatic third (n = 7) haemodialysis sessions.[27] In contrast,
disease of a different aetiology, such as primary paired samples of input and output MPAG concen-
biliary cirrhosis. Given the central role of the liver in trations differed significantly (mean ± SD MPAG
the pharmacokinetics of mycophenolate, more re- concentration for session 2: input 176 ± 128 mg/L vs
search is required in this area. T-tube clamping did output 115 ± 59 mg/L; for session 3: input 265 ± 112
not affect the pharmacokinetics of MPA or MPAG mg/L vs output 200 ± 96 mg/L), indicating that

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
haemodialysis was removing MPAG.[27] Removal of
MPAG by haemodialysis is likely to be most signifi-
cant in patients with markedly elevated MPAG con-
centrations.[15] According to manufacturer recom-
mendations, the mycophenolate dosage does not
need to be adjusted if haemodialysis is per-
formed.[15] Concentrations of MPAG that are al-
ready high would be even higher in the absence of
this procedure.
The impact of peritoneal dialysis on the
pharmacokinetics of MPA has been investigated in a
small study involving five kidney transplant recipi-
ents over two consecutive 12-hour periods (with and
without peritoneal dialysis).[100] Following initiation
of peritoneal dialysis in three patients with severe
renal impairment (GFR <10 mL/min), MPA AUC12
decreased by 59% and MPAG AUC12 decreased up
to 26%.[100] No substantial changes were observed in
either MPA or MPAG AUC12 in two patients with
GFR >40 mL/min.[100] MPA was found only in trace
amounts in the peritoneal ultrafiltrate, although the
cumulative amount of MPAG removed approached
up to 2g per 12 hours.[100] Cumulative loss of MPAG
was suggested as the main cause of reduction in
MPA AUC12 in patients with severe renal impair-
ment.
5.5 Ethnicity
Reduced efficacy, judged by a higher rate of
acute rejection, has been observed in African Amer-
icans compared with Caucasian patients receiving a
fixed mycophenolate mofetil 1g dose twice daily
following renal transplantation.[101,102] Two studies
have investigated the influence of ethnicity on the
pharmacokinetics of MPA.[95,103] Briefly, dose-
normalised MPA AUC and oral clearance did not
differ significantly in 13 African Americans com-
pared with 20 Caucasians over 90 days following
renal transplantation.[95] Free MPA AUC and free
fraction were also comparable. No significant differ-
ence in dose-normalised MPA or MPAG AUC12
was observed in 39 African Americans compared
with 43 Caucasians at least 6 months after kidney
transplantation.[103] MPA pharmacokinetics have
not been compared across other ethnic populations.
The impact of race on UGT and MRP-2 function is
an area requiring further investigation.
© 2007 Adis Data Information BV. All rights reserved.
29
5.6 Gender
No significant difference in dose-normalised
MPA or MPAG AUC12 was observed in 47 male
compared with 35 female stable kidney transplant
recipients (>6 months post-surgery).[103] Similarly,
mean dose-normalised MPA AUC12 was not signifi-
cantly different between males (n = 79) and females
(n = 41) when data from several studies were
pooled, according to manufacturer product informa-
tion.[3] The influence of patient gender on the
pharmacokinetics of mycophenolate mofetil has
been investigated in three population pharmacoki-
netic analyses, two of which found no significant
influence.[93,104] An 11% increase in MPA clearance
in males was reported in the third.[105] The average
MPA : MPAG concentration ratio was higher in
males (15.0 ± 2.2) compared with females (7.7 ±
0.9) in one study involving 100 renal transplant
recipients 1–36 months post-surgery, suggesting
that MPA glucuronidation may be faster in
males.[106] It was postulated that oestrogen may
compete with MPA for UGT binding sites, slowing
MPA metabolism in females.[106]
5.7 Co-Morbidities
Seven patients with cystic fibrosis required, on
average, a 30% higher dose of mycophenolate mofe-
til (in combination with tacrolimus) to achieve ther-
apeutic concentrations similar to those of six
weight-matched subjects with emphysema in one
study involving long-term lung transplant recipi-
ents.[107] Gastrointestinal disturbances are likely to
be responsible for poor drug absorption in the for-
mer. Hepatic disturbances and decreased small bow-
el reabsorption may contribute to a curtailing of the
metabolic process. Cystic fibrosis patients may also
have lower serum albumin levels resulting in in-
creased plasma clearance of free drug.[107]
Two investigations have reported no significant
difference in MPA pharmacokinetics in diabetic
compared with non-diabetic renal transplant recipi-
ents.[103,108] In another study, MPAG pharmacoki-
netics in such patients were also similar.[108]
5.8 Hypoalbuminaemia
Hypoalbuminaemia, common in the first few
weeks after liver transplantation, reduces the num-
Clin Pharmacokinet 2007; 46 (1)
30
ber of protein binding sites available to MPA and
MPAG. Increased MPA free fraction has been asso-
ciated with decreased serum albumin in vitro[19] and
in vivo.[22,25,32,76] In vitro, MPA free fraction in-
creased approximately 41-fold when human serum
albumin was reduced from its normal physiological
concentration of 41.4 g/L to 0.07 g/L.[19] MPA free
fraction increased 2.2-fold when serum albumin was
reduced to 20.7 g/L.[19] A significant relationship
between low serum albumin and increased percent-
age free MPA was reported in a study of 42 adult
kidney transplant recipients in the early post-trans-
plant period.[25] A cut-off value for serum albumin
of 31 g/L was identified, below which MPA free
fraction was considered to be significantly elevated
(defined as ≥3%; 20% above the reported upper
normal limit [1–2.5%]).[25] Below this cut-off, se-
rum albumin is a good predictor of altered free MPA
percentage, with sensitivity and specificity of 0.75
and 0.80, respectively.[25] It was suggested that a
serum albumin of ≤31 g/L could be used to predict
which patients are likely to have an abnormally
elevated MPA free fraction, in whom clinicians
should consider monitoring free MPA concentra-
tion.[25]
5.9 Hyperbilirubinaemia
Although it is difficult to find an original research
study that has specifically investigated hyperbiliru-
binemia as a factor influencing the pharmacokinet-
ics of MPA, it has been suggested that high bilirubin
concentrations may also displace MPA from serum
albumin binding sites.[29] Some support for this can
be found in a single-dose pharmacokinetic study of
oral mycophenolate mofetil in 18 patients with com-
pensated alcoholic cirrhosis.[97] While it was sug-
gested that cirrhosis did not significantly affect plas-
ma protein binding of MPA or MPAG, the mean
free fraction of MPA in plasma from patients with
moderate to severe compensated hepatic cirrhosis
ranged from 2.7% to 3.0% higher than that normally
observed in healthy individuals.
5.10 Time After Transplant
In renal transplant patients, the mean AUC12 of
total MPA has been reported to be at least 30–50%
lower in the first few weeks post-transplant than in
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
the later period (1–6 months post-trans-
plant).[15,109,110] Change in MPA AUC12 over time is
likely to be a result of a number of factors, including
improvement in renal function and hy-
poalbumineamia, reduction in corticosteroid dosage
and dosage of nephrotoxic ciclosporin and
tacrolimus.
One study in 100 renal allograft recipients sug-
gested that long-term changes in MPA exposure in
combination with tacrolimus and corticosteroids
may be dose dependent.[111] For patients receiving
mycophenolate mofetil 2g daily, MPA AUC12 in-
creased by a mean of 39.7% in the first 6 weeks after
transplantation, but in a 1g dosage group, AUC12
increased by only 17.1%.[111] By 3 months, the MPA
AUC12 increase had ceased in the mycophenolate
mofetil 1g dose group.[111] However, the study in-
vestigators did not simultaneously measure MPAG
and MPA free fraction, which might have shed some
light on the underlying mechanism of their findings.
5.11 Interactions with Other
Immunosuppressant Drugs
The pharmacokinetics of mycophenolate are in-
fluenced by concomitant immunosuppressant ther-
apy (table IV). Higher MPA concentrations have
been observed in animal studies and in transplant
patients receiving mycophenolate alone and in com-
bination with tacrolimus or sirolimus than in those
receiving ciclosporin in combination with mycophe-
nolate.[112-124] MPA Ctrough is significantly higher in
patients receiving tacrolimus and sirolimus than in
those receiving ciclosporin. The second MPA peak
due to enterohepatic circulation is more pronounced
in patients receiving tacrolimus or sirolimus co-
therapy, but is generally not completely absent in
patients on ciclosporin.[85,107,114,116,118,121,122,125,126]
It was suspected initially that tacrolimus co-ad-
ministration increased MPA AUC and Ctrough
through inhibition of glucuronidation.[121,127,136] It
has subsequently been demonstrated that ciclosporin
inhibits biliary secretion (postulated to be an active
process) of MPAG by the MRP-2 transport-
er.[48,113,117,137] This leads to impaired excretion of
MPAG in the bile and reduced enterohepatic recir-
culation of MPAG back to MPA.[48,113-115,123,137]
Clin Pharmacokinet 2007; 46 (1)
 Table IV. Pharmacokinetic (PK) parameters for mycophenolic acid (MPA) in different transplant groups for patients receiving different concomitant medicationsa
No. of Dose Concomitant Time post- Ctrough AUC12 Other relevant Reference
patients (twice daily) medication transplant (mg/L/dose)b (mg • h/L/dose)b PK parametersb
Adult kidney
18 1g MMF TAC 2.8 ± 1.3 50 ± 17 127
7 1g MMF CIC (Sandimmune) 1.2 ± 1.0 32 ± 17
5 1g MMF CIC (Neoral) 1.1 ± 0.4 41 ± 12
5 1.7 ± 0.3 g/d MMF TAC 3.4 ± 1.3 121
10 1.5 ± 0.5 g/d MMF CIC 1.9 ± 1.1
51 0.5g MMF TAC <3mo to >2y 3.2 ± 2.2 43.3 ± 12.2 AUC4: 23.2 ± 10.6 mg • h/L 126
97 1g MMF CIC <3mo to >2y 1.7 ± 1.0 33.6 ± 20.9 AUC4: 21.0 ± 16.7 mg • h/L
31 0.5g MMF TAC >1y CL/F: 11.9 L/h 128
33 1g MMF CIC >1y CL/F: 14.1 L/h
13 1.7–2 g/d MMF SIR 1mo 4.6 ± 2.4 79 ± 29c 112

© 2007 Adis Data Information BV. All rights reserved.

17 1.9–2 g/d MMF CIC 1mo 1.6 ± 0.6 51 ± 18c
12 0.5–2 g/d MMF SIR 1mo 3.8 [2.1, 5.5]c 51.1 [39.8, 62.3]c 116
19 0.5–2 g/d MMF CIC 1mo 1.5 [1.1, 1.9]c 34.0 [28.1, 39.9]c
26 0.5–2 g/d MMF CIC, COR 6mo 2.0 ± 1.3c 50.9 ± 22.4c 129
26 0.5–2 g/d MMF CIC, COR 9mo 2.2 ± 1.5c 55.0 ± 24.2c
26 0.5–2 g/d MMF CIC 21mo 3.1 ± 2.4c 66.7 ± 30.9c
12 0.5–2 g/d MMF CIC, COR 21mo 1.6 ± 0.8c 45.5 ± 13.7c
PK and PD of Mycophenolate in Solid Organ Transplantation

13 1g MMF CIC 5d 34.5 ± 8.7 130

14 1g MMF CIC (n = 12), TAC (n = 2), 5d 33.7 ± 11.4
iron concomitant with MMF
13 1g MMF CIC (n = 7), TAC (n = 6), 5d 32.1 ± 8.1
iron 4 hours after MMF
10 1g MMF CIC (n = 6), TAC (n = 3), >6mo 89.5 ± 27.8 131
SIR (n = 1)
10 1g MMF CIC (n = 6), TAC (n = 3), >6mo 91.9 ± 30.4
SIR (n = 1), iron
concomitant with MMF
10 1g MMF CIC (n = 6), TAC (n = 3), >6mo 96.0 ± 31.7
SIR (n = 1), iron 4 hours
after MMF
10 1g MMF TAC 5d 1.6 (1.4–3.0)d AUC6: 25.6 ± 11.1 mg • h/L 32
32 1g MMF CIC 5d 0.8 (0.6–1.3)d AUC6: 20.8 ± 8.4 mg • h/L
29 1g MMF TAC 3d 2.0 ± 1.5 36.8 ± 11.1 125
21 1.5g MMF TAC 3d 4.0 ± 3.1 43.1 ± 9.0
94 1g MMF CIC 3d 1.2 ± 0.9 30.1 ± 9.7
22 1.5g MMF CIC 3d 1.2 ± 0.6 33.8 ± 10.0

Continued next page

Clin Pharmacokinet 2007; 46 (1)

31
 Table IV. Contd 32
No. of Dose Concomitant Time post- Ctrough AUC12 Other relevant Reference
patients (twice daily) medication transplant (mg/L/dose)b (mg • h/L/dose)b PK parametersb
15 1g MMF SIR >6mo 4.7 ± 2.4 70.9 ± 19.3 118
12 1g MMF CIC >6mo 2.8 ± 1.6 51.7 ± 16.7
19 1g MMF CIC, COR 1.5 (0.4–3.7)d 119
19 1g MMF COR 3.2 (0.3–7.8)d
14 1g MMF CIC 1.8 (0.5–6.0)d
12e 0.72mg EC-MPS TAC >9mo 2.0 ± 1.0 58.8 ± 25.2 122
12e 0.72mg EC-MPS CIC >9mo 1.1 ± 0.9 47.6 ± 15.9
8 Not stated TAC, SJW 4.7 (1.9–5.8; 69.9 (56.0–81.7; 132
25–75th percentile) 25–75th percentile)
8 Not stated TAC 2.9 (2.6–6.0; 73.2 (54.8–86.6;
25–75th percentile) 25–75th percentile)
40 1g MMF CIC, DAC 28d AUC8: 30.1 ± 13.3 mg • h/L 84

© 2007 Adis Data Information BV. All rights reserved.

21 1g MMF CIC 28d AUC8: 31.1 ± 12.4 mg • h/L
40 1g MMF CIC, DAC 56d AUC8: 37.7 ± 18.2 mg • h/L
21 1g MMF CIC 56d AUC8: 35.7 ± 14.0 mg • h/L
22 1g MMF CIC >7d 1.5 48.2 ± 10.7 133
7 1g MMF TAC >7d 2.5 60.9 ± 11.7

Paediatric kidney
14 555 ± 289 mg/m2/d MMF TAC 24d 4.8 ± 2.9 63 ± 23 AUC: 0.12 ± 0.04 115
mg • h • m2/L • mgc
15 1158 ± 301mg/m2/d MMF CIC 18dd 3.6 ± 2.2 63 ± 29 AUC: 0.07 ± 0.04
mg • h • m2/L • mgc
13 866 ± 401mg/m2/d MMF No 22dd 4.4 ± 1.5 65 ± 19 AUC: 0.08 ± 0.03
mg • h • m2/L • mgc

Paediatric liver
11 250mg (65–500) MMF TAC >6mo 1.4 (0.3–3.0)d 26.0 (7.7–75.8)d AUC: 104 (60–152) mg • h/ 85
L • gc,d
10 500mg (250–1000) MMF CIC >6mo 1.7 (0.7–2.7)d 29.2 (17.7–55.0)d AUC: 63.8 (26.9–110)
mg • h/L • gc,d

Adult heart-lung
1 3g MMF TAC, RIF 92d 0.2 18.4 AUC: 6.1 mg • h/L • gc 134
1 1.5g MMF TAC 105d 1.6 29.6 AUC: 19.7 mg • h/L • gc

Adult lung
14 21 mg/kg/d MMF TAC Up to 2y 2.7f 107
16 25 mg/kg/d MMF CIC Up to 2y 1.2f

Continued next page

Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
PK and PD of Mycophenolate in Solid Organ Transplantation 33

ciclosporin; CL/F = apparent oral clearance; COR = corticosteroid; Ctrough = trough concentration; DAC = daclizumab; MMF = mycophenolate mofetil; RIF = rifampicin (rifampin);
AUC4 = area under the concentration-time curve from 0 to 4 hours; AUC6 = AUC from 0 to 6 hours; AUC8 = AUC from 0 to 8 hours; AUC12 = AUC from 0 to 12 hours; CIC =
Reference

One study has reported that increasing dosage of

mycophenolate mofetil may not change exposure to
114

135
MPA in patients receiving concomitant ciclosporin,
suggesting that active biliary secretion of MPA may
be a non-linear process.[125] Proportionately more of
Dose-to-Ctrough ratio: 0.56

Dose-to-Ctrough ratio: 0.90

the AUC of MPA may be due to enterohepatic

reabsorption at higher MPA dosages. If so, inhibi-
PK parametersb

tion of this process by ciclosporin would be most

Other relevant

(0.11–14.3)d

(0.11–8.33)d

pronounced at higher MPA doses. A negative corre-

lation between dose-normalised MPA AUC and
ciclosporin AUC has also been reported in paedia-
tric renal transplant patients, again suggesting dose-
dependent inhibition by ciclosporin of the biliary
transport of MPAG.[77] Further research is required.
(mg • h/L/dose)b

Exposure to MPA when mycophenolate is given

in combination with ciclosporin is about 30–40%
69 ± 18
53 ± 11
AUC12

lower than when the drug is given alone or co-

administered with tacrolimus or
sirolimus.[115,116,118,120,122,123,138] A higher dose of
mycophenolate is required with ciclosporin than
with tacrolimus or sirolimus to achieve similar con-
3.2 (0.3–9.8)d

2.0 (0.3–8.9)d
(mg/L/dose)b

centrations or exposure to MPA.[107,138,139]

3.3 ± 1.6
2.4 ± 1.0
Ctrough

Ciclosporin inhibition of MPA enterohepatic re-

cycling and subsequent MPAG accumulation could
lead to difficulty in interpreting measured total MPA
exposure.[32,85] Accumulated MPAG will displace
Time post-
transplant

1–192mo

1–192mo

8–208mo
8–208mo

MPA from binding sites, leading to an increase in

b Values are expressed as mean ± SD [95% CI] unless specified otherwise.

SEV = sevelamer; SIR = sirolimus; SJW = St John’s wort; TAC = tacrolimus.

MPA free fraction.[2,22,27] Patients receiving con-

comitant ciclosporin could be predicted to have an
a Studies in healthy volunteers are described in the main text only.

elevated free MPA fraction and a higher total MPA

concentration, but possibly the same free MPA con-
centration, as tacrolimus- or sirolimus-treated pa-
tients. At higher mycophenolate doses, more MPAG
Concomitant

will accumulate, displacing more MPA from bind-

medication

CIC, SEV

ing sites and possibly causing an even greater arte-

fact of apparently lower total MPA exposure. This
TAC

CIC

CIC

e Same patients, randomised cross-over.

may be another possible explanation for the lack of

increase in total MPA exposure observed in patients
500mg, 750mg or 1g MMF

500mg, 750mg or 1g MMF

Adult (3) and paediatric (6) kidney

receiving concomitant ciclosporin therapy when the

Adult kidney (120) and lung (20)

1300 ± 592 mg/d MMF

1300 ± 592 mg/d MMF

f Graphical values interpreted.

mycophenolate mofetil dose was increased from 2g

to 3g.[125]
Other immunosuppressants that are invariably
patients (twice daily)

c Dose-normalised.

included in prescribing protocols with mycopheno-

d Median (range).

late are the corticosteroids. Corticosteroids can in-

Table IV. Contd
Dose

duce expression of a number of enzymes, including

UGT, which may interfere with MPA disposi-
tion.[129] In a prospective study of 26 adult kidney
No. of

107
33

transplant recipients, MPA exposure was measured

9
9

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (1)
34
at 6 months after transplant when patients were
receiving relatively high doses of methylprednisone,
at 9 months when the corticosteroid dose was being
tapered, and again at 21 months following with-
drawal of corticosteroids.[129] A second group of
patients still receiving corticosteroid therapy at 21
months post-transplant were included as a con-
trol.[129] Exposure to MPA increased as corticoste-
roid doses were tapered and then withdrawn. The
control group had MPA exposure very similar to the
6-month study group.[129] High doses of corticoste-
roids may be inducing UGT activity and increasing
the apparent clearance of MPA or, alternatively,
reducing the bioavailability of mycophenolate.[129]
A second study has reported no difference in MPA
Ctrough in patients who have discontinued
prednisone compared with those still receiving
0.1 mg/kg in combination with ciclosporin.[140]
However, in this study, relatively low corticosteroid
doses were used.
5.12 Interactions with Other Co-Medications
Several other drug interactions with mycopheno-
late have been reported.
5.12.1 Resins and Binders
One phosphate binder, an absorbent resin, seve-
lamer, has been evaluated for its effects on the
pharmacokinetics of MPA.[135] Exposure to MPA
decreased by an average of 25% after single and
repeated concomitant dosing with sevelamer.[135]
This was proposed to be attributed to reduced gas-
trointestinal uptake of mycophenolate mofetil. Al-
ternatively, sevelamer may interfere with MPA en-
terohepatic recycling. According to manufacturer
‘data on file’, cholestyramine also influences MPA
concentrations because of binding and/or interfer-
ence with enterohepatic recycling.[15]
5.12.2 Metal Ions
A 50% decrease in exposure to MPA was report-
ed in one study in healthy male volunteers (n = 6)
who received calcium polycarbophil.[141] This was
suggested to be a result of chelation between
mycophenolate mofetil and calcium ions in the gas-
trointestinal tract.[141] A similar mechanism has been
proposed for a reported interaction between
mycophenolate mofetil and iron ions.[142] Co-admin-
istration of sustained-release ferrous sulfate tablets
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
with mycophenolate mofetil resulted in a 90% de-
crease in MPA exposure in seven healthy volun-
teers.[142] However, this finding could not be repli-
cated in a randomised study in renal transplant re-
cipients.[130] MPA exposure was similar in patients
receiving mycophenolate mofetil alone, concomi-
tantly with sustained-release ferrous sulfate, and 4
hours apart from sustained-release ferrous sul-
fate.[130] A second study in renal transplant recipi-
ents also reported no change in MPA exposure when
sustained-release ferrous sulfate was co-adminis-
tered with mycophenolate mofetil.[131] Such findings
may be explained by the different subject groups
involved (patients vs healthy volunteers). As op-
posed to healthy volunteers, transplant recipients
may be receiving other therapy, food or drink, which
could interfere with chelation (or compete for chela-
tion with ions). Transplant recipients are also likely
to be iron-deficient, which is known to change iron
absorption, possibly leaving less iron in the gut for
the proposed interaction observed in healthy volun-
teers. Furthermore, the healthy volunteers who were
studied received only single mycophenolate mofetil
doses, while patient studies were conducted after
steady-state concentrations of MPA had been
achieved. Similar considerations could apply to the
reported interaction with calcium polycarbophil.[141]
This study was also conducted in a small number of
healthy, fasting volunteers; the decrease in
mycophenolate mofetil absorption that was seen
may not be relevant for transplant recipients.
5.12.3 Rifampicin (Rifampin)
In one case report, a 2-fold reduction in MPA
exposure was reported when rifampicin (rifampin)
was co-administered.[134] Rifampicin may induce
UGT, which is responsible for metabolising MPA to
MPAG, MRP-2 (which is involved in MPAG biliary
excretion) or other pathways of elimination such as
urinary excretion of MPAG. In this patient, enter-
ohepatic recycling was essentially not occurring
when rifampicin was co-administered.[134] Further
investigation is required in other transplant patients
receiving similar inducers of glucuronidating en-
zymes and other elimination pathways.
5.12.4 Antacids
There has been one report of reduced bioavai-
lability of mycophenolate mofetil when antacids
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
were co-administered.[99] This study was performed
in rheumatoid arthritis sufferers given a single dose
of mycophenolate mofetil. MPAG concentrations
reduced in parallel with MPA exposure (a decrease
in AUC of about 15%), suggesting a drug interaction
due to chelation rather than interference with metab-
olism or recycling.[99]
5.12.5 Antivirals
No statistically significant difference in the con-
centration-time profile of MPA was observed when
it was co-administered with aciclovir or valaciclovir
in a study in 15 healthy male Caucasian volun-
teers.[143] AUC of MPAG reduced by 12% in sub-
jects receiving valaciclovir.[143] This is unlikely to be
of clinical relevance except in patients with im-
paired renal function in whom MPAG may accumu-
late. A second study reported no change in MPA
apparent clearance when ganciclovir was co-admin-
istered with a single dose of mycophenolate mofe-
til.[144]
5.12.6 St John’s Wort
One study to date has investigated the effect of a
complementary medicine on the pharmacokinetics
of MPA.[132] Once-daily dosing of St John’s wort
extract (600mg) for 14 days had no effect on MPA
exposure in renal transplant recipients.[132]
5.12.7 Antibacterials
Norfloxacin, metronidazole and a combination of
norfloxacin and metronidazole have been reported
to reduce MPA AUC by an average of 10%, 19%
and 33%, respectively, compared with mycopheno-
late mofetil alone, in healthy subjects.[49] MPAG
AUC decreased on average by 10%, 27% and 41%
with these respective combinations compared with a
control period.[49] Mycophenolate mofetil AUC also
decreased in six liver transplant recipients following
administration of a 21-day antibacterial regimen
(nystatin, tobramycin and cefuroxime) for selective
bowel decontamination.[145] Inhibition of gut bacte-
ria that normally produce and release significant
quantities of glucuronidases is the likely cause of
these drug-drug interactions.
5.13 Pharmacogenetic Variability
Processes such as glucuronidation and active bili-
ary secretion of MPA are likely to be under genetic
© 2007 Adis Data Information BV. All rights reserved.
35
control, and hence another factor influencing varia-
bility may be between-subject genetic differ-
ences.[44,46,48,146] In the future, pharmacogenetic pro-
filing may be used as an aid to accurate dosing in
order to ensure optimal immunosuppression.[2,147,148]
Marked between-subject differences in UGT ex-
pression and glucuronidation activity have been
found in adults.[149] A variation of 17-fold in the
amount of UGT1A9 protein in adult human livers
has been reported.[146] MPA glucuronidation activity
in hepatic microsomes differs by more than 9.5-fold
and correlates significantly with UGT1A9 protein
levels.[146] Single nucleotide polymorphisms (SNPs)
have been discovered in the coding and promoter
region of the UGT1A9 gene. Of these UGT1A9
promoter SNPs, –2152C>T and –275T>A SNP have
the strongest association with hepatic UGT1A9 pro-
tein content and occur in approximately 15% of the
Caucasian population.[146] Further investigation is
required in other ethnic groups. Carriers of these
SNPs have roughly 2-fold higher UGT1A9 protein
levels compared with non-carriers.[146] In vitro MPA
glucuronidation activity is 2.1-fold higher in
–2152C>T/–275T>A carriers than in non-carri-
ers.[146] Conversely, UGT activity for MPA was
significantly lower in one individual possessing a
UGT1A9*3 coding region allele (T98C), indicating
possibly decreased enzyme activity with this muta-
tion.[146] The UGT1A9*3 polymorphism has been
estimated to be present in <5% of Caucasian popula-
tions.[150,151]
The impact of UGT1A9 SNPs on MPA
pharmacokinetics has been evaluated in one study of
95 Caucasian renal transplant patients.[46] MPA
AUC12 on day 7 post-transplant was compared in
recipients carrying either or both T-275A and C-
2152T polymorphisms (heterozygous or homozy-
gous) as opposed to non-carriers.[46] MPA AUC12
was also compared in UGT1A9*3 (T98C) carriers in
comparison with non-carriers.[46] Patients received
mycophenolate mofetil 1g (n = 63) or 2g (n = 32)
daily, tacrolimus and oral methylprednisolone. In
patients receiving mycophenolate mofetil 1g daily,
the presence of the UGT1A9 SNPs T-275A or C-
2152T caused no detectable difference in MPA
AUC12.[46] In the 2g group, a significant decrease in
MPA AUC12 was observed in those who carried
either the T-275A or C-2152T polymorphism (or
Clin Pharmacokinet 2007; 46 (1)
36
both) compared with those who did not (MPA
AUC12 31.7 ± 17.6 mg • h/L [n = 6] vs 63.6 ± 30.9
mg • h/L [n = 26]).[46] A higher MPA AUC12 was
seen in individuals who carried the UGT1A9*3 SNP
compared with those who did not in the mycopheno-
late mofetil 1g dosage group (78.7 ± 18.7 mg • h/L
[n = 2] vs 42.5 ± 23.4 mg • h/L [n = 61]).[46] In this
study, it appeared that reduction in MPA exposure in
carriers of the UGT1A9 –2152C>T and –275T>A
SNPs resulted, in part, from a decrease in enterohep-
atic recirculation. This suggests that the SNPs
caused an increase in UGT activity in the intestinal
wall, rendering deglucuronidation of MPAG (and
subsequent MPA reabsorption) less effective. The
genetic effect of MPA exposure was only apparent
in patients taking mycophenolate mofetil 2g, indi-
cating dose-dependency.[46]
However, findings from this study are not con-
clusive, and more research is required. The use of an
enzyme immunoassay for MPA concentration mea-
surement may have influenced the study results,
with MPA concentration possibly approximately
10% higher as a result of assay cross reactivity with
AcMPAG.[152] AcMPAG is mainly generated by
UGT2B7 metabolism. It is not known if UGT1A9
and UGT2B7 activity are related. Other factors that
influence the pharmacokinetics of MPA, such as
renal function, serum albumin levels and corticoste-
roid dosage, are also likely to be most variable in the
early post-transplant period. It is also possible that
other as yet unidentified functional polymorphisms
located elsewhere, and in linkage disequilibrium
with the T-275A and C-2152T SNPs, could have
caused the changes observed in MPA exposure.
Further explanation is needed as to why the effect of
T-275A and C-2152T SNP was only apparent in
patients on a higher mycophenolate mofetil dosage.
Patient numbers in the 2g daily dosage group were
small (n = 32).[46] Concurrent SNPs of other UGTs
involved in MPA metabolism, such as UGT1A8 and
UGT2B7, need to be systemically examined, as do
populations other than Caucasians. Whether a genet-
ic effect is also relevant during ciclosporin co-ther-
apy is a point for further investigation. Genetic
variability in MRP-2 has also been reported. The
effects of MRP-2 SNPs on MPA and MPAG active
biliary excretion, gastrointestinal reabsorption and
active tubular secretion are unknown.
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
6. Population Pharmacokinetic Studies
To date, seven population pharmacokinetic anal-
yses of mycophenolate have been published (table
V). All involved mycophenolate mofetil and were
performed in kidney transplant recipi-
ents.[90,93,104,105,128,153,154] In these studies, nonlinear
mixed-effects modelling techniques have been used
to obtain mean population estimates for parameters,
such as apparent oral clearance (CL/F), apparent
volume of administration after oral administration
(V/F), absorption rate constant (ka) and tlag; to
characterise between-subject (BSV) and between-
occasion (BOV) pharmacokinetic variability; and to
identify and model the influence of demographic
and clinical factors (covariates) on pharmacokinetic
variability.
A bi-exponential elimination model with an ab-
sorption lag time was selected to describe the
pharmacokinetics of mycophenolate mofetil in 22
patients in their first month post-transplant.[90] Large
BOV in ka and tlag was evident: 184% and 33%,
respectively. To account for the complex absorption
of MPA, time-dependant absorption, maximum ef-
fect (Emax), Weibull and dual sequential first-order
absorption models were trialled. None improved the
fit of the data. Models allowing time-dependent
clearance and enterohepatic recirculation were also
tested but not retained. This study had a small num-
ber of subjects, some with missing demographic
information. No formal evaluation of model appro-
priateness was undertaken after the final model was
obtained.
In another study, a bi-exponential elimination
model with zero-order absorption and an absorption
duration parameter was selected to describe the
pharmacokinetics of mycophenolate mofetil in 60
stable adult kidney transplant recipients.[104] The
CL/F of MPA was positively correlated with patient
bodyweight.[104] However, consideration of
bodyweight only reduced BSV in CL/F by 6.6%,
suggesting that administration of mycophenolate on
a per kilogram basis would be of limited value.[104]
Residual random variability (RRV) associated with
the final model was relatively high (2.0 mg/L),
indicating that a significant amount of
pharmacokinetic variability was as yet unaccounted
for.[104] Model predictions were tested using Baye-
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
sian forecasting of MPA AUC12 in 10 independent
patients (see section 9 for details).
The data were best described using a bi-exponen-
tial elimination model with first-order absorption in
a third study of 117 subjects in their first week post-
transplant.[93] MPA CL/F decreased significantly
with increasing serum albumin (1.42 L/h reduction
in total plasma CL/F with each 1 g/L increase in
albumin) and was 27% greater in patients receiving
ciclosporin than tacrolimus. The final model RRV
was relatively high (41%), probably due in part to
difficulty in characterisation of MPA enterohepatic
recirculation. Final model predictions were non-
biased but imprecise during predictive performance
testing.[93]
Different gamma distributions were investigated
to fit the absorption profile of MPA in a population
study of 44 renal transplant recipients.[153] The re-
sults are not shown in table IV as not all parameter
values are readily convertible to values from other
studies. A single exponential elimination model
with double gamma absorption (which allows for
two absorption phases, one slower than the other)
best fit the data collected in the immediate post-
transplant period. Beyond 3 months, a bi-exponen-
tial elimination model with single gamma absorp-
tion and a single exponential elimination model with
double gamma absorption performed similarly.
Mean ± SD CL/F was 40.2 ± 18.9 L/h (day 3), 42.9 ±
15.2 L/h (day 7), 34.1 ± 13.8 L/h (day 30) and 31.6 ±
15.4 L/h (>3 months).[153] Pharmacokinetic parame-
ters exhibited high BSV (40–66% for the estimated
Ctrough and 41–76% for the absorption parameters).
Mycophenolate mofetil pharmacokinetics were
best described using a bi-exponential elimination
model with first-order absorption and an absorption
lag time in a population study of 41 paediatric and
adolescent kidney transplant recipients aged 2–21
years.[154] Thirty-two patients were used to develop
the model, and a further nine were used to test its
predictive performance. Inclusion of an absorption
duration parameter and enterohepatic recirculation
model were examined but not selected. MPA appar-
ent central compartment volume of distribution (V1/
F) positively correlated with patient bodyweight.
The majority of children received ciclosporin co-
therapy and three children received tacrolimus.
© 2007 Adis Data Information BV. All rights reserved.
37
Mycophenolate mofetil pharmacokinetics were
best described by a bi-exponential elimination
model with time-lagged first-order absorption in the
largest population study to date.[105] 6523 plasma
concentration-time points were obtained from 140
patients. MPA CL/F was significantly correlated
with patient creatinine clearance, plasma albumin
concentration, gender and ciclosporin dose.
Mycophenolate mofetil V1/F was influenced by pa-
tient creatinine clearance and plasma albumin con-
centration. An internal validation technique was
used to test the predictive performance of the final
model. Mean validation and final model parameter
estimates differed by no more than 3%.
Finally, one study has used population modelling
to characterise the role of enterohepatic recycling in
the interaction between mycophenolate mofetil and
ciclosporin and tacrolimus.[128] MPA and MPAG
concentration-time curves were measured during the
first year post-transplant in 64 subjects. MPA and
MPAG concentration-time data were fitted to a four-
compartment model in which a rate constant
describing the transfer from the fourth to the first
compartment (k41) [signifying enterohepatic re-
cycling] could be introduced. The model was signif-
icantly improved by the introduction of a k41 param-
eter in the case of tacrolimus administration (n = 31)
but not ciclosporin administration (n = 33), provid-
ing supportive evidence for inhibition of enter-
ohepatic recycling by ciclosporin. Under this model,
no significant difference in MPA CL/F was ob-
served between tacrolimus and ciclosporin co-ad-
ministration (11.9 vs 14.1 L/h). Total CL/F of
MPAG was lower during ciclosporin co-administra-
tion (1.45 vs 0.92 L/h, respectively); however, there
was no difference in renal clearance of MPAG (1.09
vs 0.92 L/h, respectively). A correlation was found
between patient creatinine clearance and the elimi-
nation rate constant of MPAG. No formal evaluation
of model appropriateness was undertaken.
In the majority of population pharmacokinetic
studies to date, a bi-exponential elimination model
has been selected to describe the pharmacokinetics
of mycophenolate. Mean mycophenolate mofetil
CL/F estimates range from 14.1 to 34.9 L/h in adults
receiving ciclosporin co-therapy and from 11.9 to
25.4 L/h in adults on tacrolimus. Serum albumin
concentration, patient bodyweight and ciclosporin
Clin Pharmacokinet 2007; 46 (1)
 38
Table V. Population pharmacokinetic (PK) studies of mycophenolate mofetil
Variable Shum et al.[90] Le Guellec et al.[104] Staatz et al.[93] Payen et al.[154] Van Hest et al.[105] Cremers et al.[128]
1mo post-renal >6mo post-renal 1wk post-renal 12–3754d post-renal 0–140d post-renal >1y post-renal
transplant transplant transplant transplant transplant transplant
No. of subjects 22 adultsa,b 60 adultsa,c 117 adultsa,b,d 41 childrena,b,d 140 adultsa,b 64 adultsa,c,d

PK parametere
CL/F (L/h) 27.1 (5) 15.7f (5) 34.9a,g / 25.4d,g 17.2 (51) 33 (6) 14.1a / 11.9d
V1/F (L) 98 (13) 36 (19) 65 (7) 5f (17) 91 (7) 11.7a / 10.7d
V2/F (L) 206 (27) 137 (17) 496 (20) 237 (10) 465a / 183d
Q/F (L/h) 25.7 (13) 25.9 (36) 30.7 (10) 35 (5) 20.1a / 11.2d
α (h–1) 7.5
β (h–1) 0.0072 (29)
k21 (h–1) 0.017 (31)

© 2007 Adis Data Information BV. All rights reserved.

Duration of input (h) 0.69 (7)
ka (h–1) 2.27 (8) 0.64 (14) 0.63 (19) 4.1 (7)
Lag time (h) 0.145 (14) 0.69 (5) 0.21 (1)
VMPAG/F (L) 5.6a / 8.9d
k40 (h–1) 0.165a / 0.122d
k41 (h–1) 0.0410d

Between-subject variabilitye
CL/F (%) 20 (62) 28 32 (29) 51 31 (15)
V1/F (%) 56 (58) 63 35 91 (13)
V2/F (%) 151 (98) 102 (25)
Q/F (%) 45 109 (21)
α (%)
β (%) 32
k21 (%) 22
Duration of input (%) 11
ka (%) 78 (28) 44 111 (15)
Lag time (%) 100

Between-occasion variabilitye
CL/F (%) 13 (74) 35 (14) 20 (11)
V1/F (%) 95 (29) 53 (17)
V2/F (%) 51 (90)
Q/F (%)

Continued next page

Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
 Table V. Contd
Variable Shum et al.[90] Le Guellec et al.[104] Staatz et al.[93] Payen et al.[154] Van Hest et al.[105] Cremers et al.[128]
1mo post-renal >6mo post-renal 1wk post-renal 12–3754d post-renal 0–140d post-renal >1y post-renal
transplant transplant transplant transplant transplant transplant
α (%)

β (%)

k21 (%)

Duration of input (%)

ka (%) 184 (21) 116 (11)

Lag time (%) 33 (343)

© 2007 Adis Data Information BV. All rights reserved.

Residual random variabilitye

Proportional 35 (61) NR 41 (4) 27 35

Additive (mg/L) 0.75 (88) 2.04 0.57 0.45 (2)

Covariates
PK and PD of Mycophenolate in Solid Organ Transplantation

WT on CL/F Albumin on CL/F WT on V1/F Gender, CLCR,

Ciclosporin on CL/F albumin, ciclosporin
dose on CL/F; CLCR,
albumin on V1/F

a Ciclosporin co-therapy.

b Liquid chromatography.

c Enzyme immunoassay.

d Tacrolimus co-therapy.

e Values are expressed as mean (% coefficient of variation).

f Based on median study weight.

g Based on median study albumin (26 g/L).

α = apparent rate constant of distribution; β = apparent rate constant of elimination; CLCR = creatinine clearance; CL/F = apparent oral clearance; k21 = transfer rate constant from
tissue compartment to central compartment; k40 = elimination rate constant of MPAG; k41 = rate transfer constant describing biliary excretion of MPAG; ka = absorption rate
constant; NR = not reported; Q/F = apparent inter-compartmental clearance; V1/F = apparent volume of distribution of central compartment after oral administration; V2/F =
apparent volume of distribution of peripheral compartment after oral administration; VMPAG/F = apparent volume of distribution of 7-O-mycophenolic acid-glucuronide; WT =
bodyweight.

Clin Pharmacokinet 2007; 46 (1)

39
40
co-therapy were the covariates most often identified
as influencing mycophenolate mofetil CL/F. Com-
plex absorption and enterohepatic recirculation of
MPA has made population modelling challenging.
High residual variability in some models can proba-
bly be attributed, in part, to difficulties in character-
ising MPA enterohepatic recirculation. In many
models, a significant amount of pharmacokinetic
variability remained unaccounted for. Further stud-
ies are required in other transplant populations and
in larger groups with more diverse subjects. Consid-
ering free as well as total MPA concentration during
modelling may give further insight into mycopheno-
late pharmacokinetics.
7. Clinical Pharmacodynamics
7.1 Efficacy
A number of studies have evaluated the relation-
ship between exposure to MPA and clinical efficacy
(table VI). Only a few studies have been unable to
detect a relationship between low MPA AUC values
and acute rejection.[62] Some of these may not have
been sufficiently powered. Similar MPA AUC12
values were observed between patients who did and
those who did not experience acute rejection in the
first 28 days post-transplant, in a prospective study
of 21 kidney transplant recipients.[155] The popula-
tion size is likely to be insufficient to detect a
difference. Neither free nor total MPA AUC from 0
to 6 hours (AUC6) could be related to rejection in a
study of 42 renal transplant patients receiving con-
comitant ciclosporin (n = 32) or tacrolimus (n = 10)
therapy.[32] Total and free MPA AUC6 were estimat-
ed on day 5 and related to rejection in the first month
post-transplant.[32] Absence of a relationship may be
because of the low number of rejection episodes in
this study.[32] Likewise, no relationship between
MPA AUC12 and acute rejection was observed in a
prospective study of 100 adult kidney transplant
recipients.[156] However, only MPA AUC on day 7
post-transplant was considered.
In some studies, tacrolimus and ciclosporin
Ctrough values across rejecter and non-rejecter
groups were not accessed or were also low, poten-
tially confounding results.[133] This is the case in an
investigation of 29 Chinese kidney transplant recipi-
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
ents in the first month after transplantation[133] and
in a prospective study of 36 renal transplant recipi-
ents in the first 2 weeks post-transplant.[158] In both
investigations, significantly lower MPA AUC val-
ues were reported in patients experiencing rejection;
however, concurrent ciclosporin and tacrolimus
Ctrough values across the groups were not examined.
In an open-label, longitudinal evaluation involving
31 paediatric kidney transplant recipients, both
AUC12 and Ctrough discriminated patients who did
and did not experience acute rejection. However,
ciclosporin Ctrough values were not examined (re-
sults not shown in table VI as they were presented in
a different format to other studies in the table).[78]
Using a high-performance liquid chromatography
(HPLC) assay, an AUC12 cut-off of 29.5 mg • h/L
had a diagnostic sensitivity of 66.7% and specificity
of 79.4%; the corresponding enzyme-multiplied im-
munoassay technique (EMIT) cut-off value was
36.1 mg • h/L.[78] In the case of MPA Ctrough, a
threshold concentration of 1.0 mg/L determined by
HPLC displayed similar sensitivity (77.8%) and
specificity (64.5%) to an EMIT value of 1.3 mg/
L.[78] In a retrospective study involving 27 kidney
transplant recipients, 27% of patients with an MPA
AUC >30 mg • h/L experienced acute rejection,
compared with 56% of those with an MPA AUC
<30 mg • h/L.[157] A single, four-point MPA AUC
was measured in the first week after transplantation
and compared with rejection outcome during the
first month. This finding, however, was confounded
by the rejecter group also having significantly lower
median ciclosporin Ctrough values.
More conclusive evidence of a relationship be-
tween acute rejection and low MPA AUC comes
from investigations that have considered immu-
nosuppressant co-therapy.[70] In a prospective study
of 38 cardiac transplant recipients, patients with
grade 2 or 3 rejection had lower mean total MPA
AUC and lower mean free MPA AUC from 0 to 2
hours (AUC2) than patients with grade 1 rejec-
tion.[70] Free MPA AUC2 was also significantly
lower in patients with grade 2 and 3 rejection com-
pared with no rejection. The prednisone dosage and
ciclosporin AUC and Ctrough were not significantly
different between groups. On average, patients were
followed-up for >300 days.
Clin Pharmacokinet 2007; 46 (1)
 Table VI. Summary of pharmacodynamic studies of mycophenolate mofetil (MMF) investigating efficacy
No. of Event Patient no. Time post- Ctrough (mg/L)a AUC12 Comments Reference
patients (no. of episodes) (sample no.) transplant (mg • h/L)a
Adult kidney
27b,c, Rejection 12 ≤1mo 27.6 ± 2.0d,e Difference in median ciclosporin 157
No rejection 15 35.1 ± 2.2e Ctrough between groups
36b,f,g Rejection 3 2wk 2.0 ± 0.9 28.2 ± 1.9d,h Both ciclosporin and tacrolimus 158
No rejection 33 0.9 ± 0.4 34.2 ± 16.8h co-therapy; difference in ciclosporin or
tacrolimus Ctrough between groups not
examined
31b,g Rejection 3 ≤3mo 1.00 ± 0.45 25.0 ± 6.2 No statistical comparison. Difference 60
Uneventful 10 1.63 ± 1.07 39.8 ± 15.3 in ciclosporin Ctrough between groups
not examined
21c,f Rejection 5 28d 32.2 ± 21.3 Difference in tacrolimus Ctrough 62

© 2007 Adis Data Information BV. All rights reserved.

No rejection 16 59.5 ± 31.1 between groups not examined
22b,c Rejection 6 (6) ≤6mo 0.53 ± 0.29d No difference in ciclosporin Ctrough 159
No adverse effects or 7 (102) 0.87 ± 0.10 between groups
rejection
39b,c Rejection 12 ≤3mo 1.45 ± 0.56 Difference in ciclosporin Ctrough 160
No rejection 27 1.22 ± 0.89 between groups not examined
PK and PD of Mycophenolate in Solid Organ Transplantation

Rejection 12 ≤1y 1.15 ± 0.53

No rejection 27 1.35 ± 0.81
33c,f Rejection 4i ≤1y 2.46 No difference in tacrolimus Ctrough 61
No rejection 4i 1.67 between groups
150b,c Rejection 11.5%j,k 6mo Target: 60.6 Difference in ciclosporin Ctrough 161
Rejection 14.9%j,k Target: 32.2 between groups not examined
Rejection 27.5%j,k Target: 16.1
32b Rejection 8.3%j 3wk Target: ≥40 No statistical comparison 162
Rejection 63.2%j Target <40
27g Rejection 3 <1y 2.3 (1.26–3.38)l Patients not receiving calcineurin 163
No rejection Control patients 3.8 (1.48–6.52)l co-therapy
on similar MMF
dosage
48b,g Rejection 18 ≤2mo 1.55 ± 0.48d No difference in ciclosporin Ctrough 164
No rejection 30 2.10 ± 0.62 between groups
29b,c,f Rejection 3 ≤1mo 40.9 ± 14.3d Difference in ciclosporin or tacrolimus 133
No rejection 26 53.9 ± 12.7 Ctrough between groups not examined

Continued next page

Clin Pharmacokinet 2007; 46 (1)

41
 Table VI. Contd 42
No. of Event Patient no. Time post- Ctrough (mg/L)a AUC12 Comments Reference
patients (no. of episodes) (sample no.) transplant (mg • h/L)a
Adult liver
147b,f,g Rejection 10 (10)i 0.5 (<0.3–1.8)d,l Difference in ciclosporin and 155
No rejection (279)i 1.4 (<0.3–7.4)l tacrolimus Ctrough between groups not
examined. Samples representing no
rejection were recorded on 279
occasions either at times patients did
not experience rejection or from
patients who were rejection free at all
times
100f,g Rejection 16 7d 2.5 ± 2.2 56.4 ± 45.4 No difference in tacrolimus Ctrough 156
No rejection 84 2.1 ± 1.5 46.0 ± 22.8 between groups

© 2007 Adis Data Information BV. All rights reserved.

42b,c,f Rejection 7 ≤1mo 18.2 ± 7.9m No difference in calcineurin Ctrough 32
No rejection 35 22.7 ± 9.4m between groups

Adult heart
38b,c Rejection grade 1 13 ≤10mo 1.24 ± 0.72 51.7 ± 17.5 No difference in ciclosporin Ctrough 70
Rejection grade 2/3 3 0.65 ± 0.15 26.1 ± 6.6n between groups
No rejection 22 1.20 ± 0.58 42.8 ± 14.0
20b,g Rejection 9 (61) 0–1y 1.36 (0.26–6.13)d,l No difference in ciclosporin Ctrough 165
No rejection 11 (54) 1.76 (0.49–7.65)l between groups
15f,g Rejection (1–2) 7 ≤6mo 2.2 ± 0.4 No difference in tacrolimus Ctrough 166
Rejection (3) 3 1.4 ± 0.2 between groups
No rejection 5 3.6 ± 0.4
215b,f,g Rejection 14.4%d,o <1y <2 Sub-therapeutic ciclosporin and 167
Rejection 3.6%o >2 tacrolimus Ctrough may confound finding

Young adult and paediatric heart

26b,f Grade 2 rejection 1.05 ± 1.0p Biopsy result excluded if calcineurin 168
Grade 1 or no rejection 2.3 ± 2.4 Ctrough considered to be low for that
period post-transplant

Paediatric kidney
40c Rejection >6mo 28.7 (15.3–57)l Information on co-therapy not 169
No rejection 38.3 (3.1–134)l provided. No statistical comparison
a Values are expressed as mean ± SD unless specified otherwise.
b Ciclosporin co-therapy.

Continued next page

Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
PK and PD of Mycophenolate in Solid Organ Transplantation 43

Likewise, an association between the risk of

acute rejection, MPA AUC12 and Ctrough was re-

AUC6 = area under the concentration-time curve from 0 to 6 hours; AUC9 = AUC from 0 to 9 hours; AUC12 = AUC from 0 to 12 hours; Ctrough = trough concentration.
ported in an open-label, longitudinal study involving
45 paediatric kidney transplant recipients (results
not shown in table VI).[80] An AUC12 cut-off of 33.8
mg • h/L in the first 1–3 weeks post-transplant had a
diagnostic sensitivity of 75% and specificity of 64%
for discriminating patients with acute rejection. The
respective discrimination threshold for MPA Ctrough
was 1.2 mg/L, with a sensitivity of 83% and speci-
ficity of 64%. Ciclosporin dosage and Ctrough were
not significantly different between rejecters and
non-rejecters. In a double-blind study of 150 pa-
tients randomly assigned to one of three target
AUC12 groups (16.1, 32.2 or 60.6 mg • h/L), 27.5%
of patients in the low MPA group experienced rejec-
tion, compared with 14.9% in the intermediate
group and 11.5% in the high group.[109] An AUC12
of 15 mg • h/L yielded 50% maximal achievable
efficacy with a 4% change in efficacy for each 1
mg • h/L change in AUC12 at the midpoint of the
logistic curve.[109] MPA Ctrough had poorer predic-
Statistically significantly different compared with no rejection and rejection grade 1 groups.

tive power for rejection outcome.[109] While there

was no difference in the mean ciclosporin dose
between the groups, the mean ciclosporin Ctrough
was not examined.[161]
A relationship between acute rejection and MPA
Statistically significantly different compared with grade 1 rejection group.

Ctrough has also been reported by

many,[155,159,164,165,167,168] but not all, investiga-
Statistically significantly different compared with no rejection group.

tors.[163] The median MPA Ctrough was not signifi-

cantly different in rejecters compared with non-
rejecters in a prospective study of 27 stable renal
transplant patients who were switched from
AUC calculated using a limited sampling strategy.

ciclosporin to mycophenolate mofetil 1 year after

Considered intra-individual patient differences.

transplantation. At periods of acute rejection, sub-

jects were matched with non-rejecting controls who
had been switched from ciclosporin to mycopheno-
Statistical difference between groups.

late mofetil at the same time.[163] Patients were fol-

lowed up for 1 year. Similarly, MPA Ctrough was not
significantly different in rejecters compared with
non-rejecters, within 3 months of transplant or dur-
Liquid chromatography.

Enzyme immunoassay.
Tacrolimus co-therapy.

ing a 1 year follow-up period, in 39 adult kidney

transplant recipients. However, the difference in
Median (range).
Incidence (%).

Incidence (%).

ciclosporin Ctrough between groups was not ex-

Table VI. Contd

amined. No significant between-occasion difference

AUC9.

m AUC6.

was found in MPA Ctrough, AcMPAG Ctrough,

MPAG Ctrough or AcMPAG : MPA ratio in 33 renal
transplant recipients at the times they did and did not
d
e

g
h

n
o
p
c

k
f

i
j

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (1)
44
experience rejection in a prospective 12-month mul-
ticentre study.[61] Rejection occurred infrequently (n
= 4 patients); therefore, this study may not have
been sufficiently powered.
In contrast, MPA Ctrough was significantly lower
in patients who experienced acute rejection com-
pared with individuals who displayed no adverse
effects or rejection in a prospective study of 22
Chinese kidney transplant recipients.[159] Patients
were followed up for 6 months. Similarly, MPA
Ctrough was significantly lower in patients with acute
rejection (n = 18), compared with those without (n =
30), in a retrospective analysis of 48 kidney trans-
plant recipients within the first 2 months post-trans-
plant.[164] In a study of 147 adult liver transplant
recipients, MPA Ctrough was significantly lower at
the times when patients experienced acute rejection
(n = 10 samples).[155] Samples representing no rejec-
tion were recorded on 279 occasions, either at the
times when patients did not experience rejection or
from patients who were rejection free at all times.
The relative risk of rejection increased 4.2-fold,
2.5-fold and 1.6-fold at a MPA Ctrough of <0.5, 1.0
and 1.5 mg/L, respectively.[155] An MPA Ctrough
lower limit of 1 mg/L was suggested in this study.
The difference in ciclosporin and tacrolimus Ctrough
between rejecters and non-rejecters was not ex-
amined.[155] In a retrospective study of 215 patients
within 1 year of transplantation, subjects with an
MPA Ctrough ≥2 mg/L had a significantly lower
incidence of rejection compared with those with an
MPA Ctrough <2 mg/L.[167] The incidence of rejec-
tion was 8.8% versus 14.9% from 0 to 6 months
post-transplant and 4.2% versus 11.3% from 6 to 12
months post-transplant in the two groups.
Two studies have been performed in heart trans-
plant recipients.[165] The median MPA Ctrough was
significantly different in patients with acute rejec-
tion compared with those without in a retrospective
study of 20 patients in the first year following cardi-
ac transplantation.[165] 147 endomyocardial biopsies
were analysed.[165] In a retrospective study of 26
young adult and paediatric heart transplant recipi-
ents, an endomyocardial biopsy grade ≥2 was asso-
ciated with significantly lower MPA Ctrough com-
pared with patients experiencing grade 1 or no rejec-
tion.[168] To verify that low calcineurin inhibitor
Ctrough did not confound the results, biopsies were
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
excluded if associated ciclosporin or tacrolimus
Ctrough was low for that particular post-transplant
period.[168] The dataset was re-analysed using a di-
chotomous MPA Ctrough cut-off of 2.5 mg/L.[168] No
patient experienced grade 2 or 3A rejection when
MPA Ctrough was >2.5 mg/L.[168]
A relationship between low MPA AUC and an
increased incidence of biopsy-proven acute rejec-
tion has been reported by several investigators. A
similar association with MPA Ctrough has also been
reported but does not appear to be as sensitive an
indicator. The majority of pharmacodynamic studies
have been performed in adult kidney transplant re-
cipients within the first year post-transplant. In most
studies, MPA exposure has been compared across
patient groups (rejecters vs non-rejecters) rather
than at the times when one individual did and did not
experience rejection. All studies have involved
mycophenolate mofetil. Based on current data (table
VI), an MPA AUC12 value >30 mg • h/L appears to
be a reasonable target to minimise rejec-
tion.[80,109,161,170]
7.2 Adverse Effects
Gastrointestinal and haematological adverse ef-
fects and infection are associated with mycopheno-
late usage (table VII). A few studies have been
unable to detect an association between MPA expo-
sure and drug adverse effects.[161] In a prospective,
randomised, double-blind, multicentre, controlled
study in 150 renal transplant patients, a dose-depen-
dent increase in adverse effects was reported in the
first 6 months post-transplant.[161] However, no sig-
nificant relationship was observed between MPA
Ctrough or AUC and adverse effects leading to pre-
mature study withdrawal.[161] In a study of 39 adult
kidney transplant recipients, MPA Ctrough was not
significantly different in eight subjects who exper-
ienced leukopenia, compared with 31 who did not,
during 1 year of follow-up.[160] Similarly, no signifi-
cant difference in mycophenolate mofetil dosage or
MPA AUC could be found in patients with and
without viral infection in a retrospective study of 21
renal transplant recipients in the first 28 days fol-
lowing transplantation.[62] However, few viral infec-
tions were detected. In one retrospective study in-
volving 27 kidney transplant recipients, 4 patients
with gastrointestinal adverse effects had significant-
Clin Pharmacokinet 2007; 46 (1)
 Table VII. Summary of pharmacodynamic studies of mycophenolate mofetil investigating adverse effects (AEs)
No. of Event Patient no. Time post- Ctrough (mg/L)a AUC12 Comments Reference
patients (sample no.) transplant (mg • h/L)a
Adult kidney
31b,c AE 21 ≤3mo 2.29 ± 1.16 62.1 ± 21.1d Difference in ciclosporin Ctrough between groups 60
Uneventful 10 1.63 ± 1.07 39.8 ± 15.3 not examined
22c,e No AE or rejection 7 (102) ≤6mo 0.87 ± 0.10 No difference in ciclosporin Ctrough between 159
AEs including infection 9 (43) 1.51 ± 0.28d groups
Infections (20) 1.41 ± 1.04d
No infection (131) 1.02 ± 0.71
Haematological AEs (25) 1.56 ± 0.96d
No haematological AEs (126) 0.97 ± 0.70
Diarrhoea (9) 1.64 ± 1.11d
No diarrhoea (142) 1.01 ± 0.68

© 2007 Adis Data Information BV. All rights reserved.

36c,b,f AEs 15 2wk 0.7 ± 0.5 39.2 ± 22.8g Both ciclosporin and tacrolimus co-therapy; 158
No AEs 21 1.0 ± 0.3 30.1 ± 8.0g difference in ciclosporin or tacrolimus Ctrough
between groups not examined
39c,e Leukopenia 8 1.40 ± 0.69 Difference in ciclosporin Ctrough between groups 160
No leukopenia 31 1.39 ± 0.77 not examined
33e,f Diarrhoea 4h ≤1y 1.81 Difference in tacrolimus Ctrough at times patients 61
PK and PD of Mycophenolate in Solid Organ Transplantation

No diarrhoea 4h 1.69 did and did not have anaemia

Leukopenia 10h 2.24
No leukopenia 10h 1.91
Anemia 19h 2.00
No anaemia 19h 2.61
27c,e GI AEs 4 ≤1mo 23.7 ± 2.4d,i No difference in median ciclosporin Ctrough 157
No GI AEs 23 33.2 ± 1.7i between groups
15c,b AEs 7 >1y 2.62 ± 0.32d Difference in tacrolimus Ctrough between groups 171
No AEs 8 4.43 ± 0.38 not examined
21e,f Infection 5 28d 61.5 ± 30.3 62
No infection 16 50.4 ± 31.6
46c,e Anemia 6–9mo 3.32 ± 2.26 No difference in ciclosporin dose, Ctrough or AUC 172
No anaemia 3.53 ± 2.57 between groups
51b,f AEs 21 ≤3mo 2.63 ± 1.58d 48.4 ± 18.5d Difference in tacrolimus Ctrough between groups 173
Uneventful 30 1.75 ± 0.82 36.0 ± 10.8 not examined
150c,e Withdrawal due to AEs 44.2%j 6mo Target: 60.6 Difference in ciclosporin Ctrough between groups 161
Withdrawal due to AEs 23.4%j Target: 32.2 not examined

Continued next page

Clin Pharmacokinet 2007; 46 (1)

45
 46
Table VII. Contd
No. of Event Patient no. Time post- Ctrough (mg/L)a AUC12 Comments Reference
patients (sample no.) transplant (mg • h/L)a
Withdrawal due to AEs 7.8%j Target: 16.1
100b,f Infection 17 7d 1.73 ± 1.52 39.7 ± 20.0 Tacrolimus AUC significantly higher in patients 156
No infection 79 7d 2.20 ± 1.36 46.9 ± 22.2 with an infection than without within the first 3mo
Infection 8 6wk 2.01 ± 1.25 45.4 ± 16.9 post-transplant
No infection 84 6wk 3.01 ± 1.97 61.5 ± 30.6
Infection 8 3mo 2.83 ± 2.15 39.2 ± 28.4
No infection 85 3mo 3.11 ± 1.55 45.1 ± 26.6
Infection 5 12mo 4.35 ± 1.55 54.6 ± 28.7
No infection 78 12mo 3.64 ± 2.88 46.7 ± 25.5
Leukopenia 5 7d 2.94 ± 0.33d 54.4 ± 11.0
No leukopenia 92 7d 2.17 ± 1.62 47.4 ± 28.0

© 2007 Adis Data Information BV. All rights reserved.

Leukopenia 6 6wk 3.16 ± 1.43 65.0 ± 26.0
No leukopenia 88 6wk 2.83 ± 1.73 59.0 ± 28.7
Leukopenia 11 3mo 4.12 ± 1.6 61.4 ± 30.9d
No leukopenia 81 3mo 2.93 ± 1.55 42.3 ± 25.3
Leukopenia 5 12mo 8.69 ± 7.95d 84.4 ± 45.6d
No leukopenia 75 12mo 3.36 ± 1.86 44.2 ± 21.9
Anemia 83 7d 2.25 ± 1.67 48.5 ± 28.7
No Anemia 15 7d 1.96 ± 0.90 44.3 ± 16.4
Anemia 72 6wk 3.14 ± 2.05 62.7 ± 30.7
No Anemia 23 6wk 2.33 ± 1.30 52.8 ± 25.2
Anemia 51 3mo 3.49 ± 1.51 49.4 ± 28.9d
No Anemia 38 3mo 2.56 ± 1.57 37.5 ± 19.4
Anemia 21 12mo 4.90 ± 2.49 61.1 ± 31.9d
No Anemia 62 12mo 3.27 ± 2.82 42.3 ± 21.3
30c,b AEs 13 2.13 ± 1.35 No difference in ciclosporin Ctrough between groups 174
No AEs 17 1.53 ± 0.67

Adult liver
147c,b,f GI AEs (42)h 1.6 (<0.3–9.5) Difference in ciclosporin and tacrolimus Ctrough 155
Leukopenia (9)h 2.8 (0.9–7.8)d,k between groups not examined. Samples
Neurological AEs (7)h 1.9 (0.6–3.3)k representing no AEs were recorded on 279
All infections (18)h 1.8 (0.3–6.0)k occasions either at times patients with AEs did
Bacterial infections (13)h 1.6 (0.3–4.4)k not experience these events or from patients
Other AEs (19)h 2.0 (0.8–5.2)d,k who were free from AEs at all times

Continued next page

Clin Pharmacokinet 2007; 46 (1)

Staatz & Tett
PK and PD of Mycophenolate in Solid Organ Transplantation
Reference 47

ly lower MPA AUC values.[157] It was suggested that

in patients with gastrointestinal toxicity, less drug
might have been absorbed, causing more local irrita-
tion.[157]
A relationship between high MPA AUC values

AUC9 = area under the concentration-time curve from 0 to 9 hours; AUC12 = AUC from 0 to 12 hours; Ctrough = trough concentration; GI = gastrointestinal.
and drug-related adverse effects has been reported in
some studies.[60] In a prospective investigation of
100 adult kidney transplant recipients, from 3
months post-transplant onwards, patients with anae-
mia and leukopenia had significantly higher MPA
AUC12 then those not experiencing these effects.[156]
A therapeutic window for MPA between 45 and 60
mg • h/L, based on abbreviated AUC measure-
ments, was suggested.[156] MPA AUC12 was signifi-
cantly higher in 21 patients with MPA-related ad-
verse effects, compared with 10 patients who had an
Comments

uneventful course in the first 3 months post-trans-

plant, in a prospective study of 31 renal transplant
recipients.[60] Adverse effects included leukopenia
(15 episodes), anaemia (7 episodes), diarrhoea (1
(mg • h/L)a

episode), oesophagitis (1 episode) and thrombo-

AUC12

cytopenia (1 episode). In a similar study by the same

research team,[173] MPA AUC12 and Ctrough were
significantly higher in 21 adult patients experienc-
ing toxicity compared with 30 patients with an une-
1.4 (<0.3–7.4)k
Ctrough (mg/L)a

ventful course in the first 3 months post-renal trans-

Statistically significantly different compared with uneventful or no AEs group.

plant. Adverse effects included thrombocytopenia (2

episodes), leukopenia (8 episodes), severe anaemia
(9 episodes) and gastrointestinal toxicity (14 epi-
Values are expressed as mean ± SD unless specified otherwise.

sodes). A threshold of toxicity was identified at

Time post-

3 mg/L (sensitivity 38.7%; specificity 91.5%) for

transplant

MPA Ctrough and at 37.6 mg • h/L for MPA AUC12

(sensitivity 83.3%; specificity 59.6%).
AUC calculated using a limited sampling strategy.

Relationships between high MPA Ctrough and

(sample no.)

Considered intra-individual patient differences.

drug adverse effects have also been reported by

Patient no.

some investigators.[155] In 147 adult liver transplant

(279)h

recipients, MPA Ctrough was significantly higher

during episodes of leukopenia.[155] There was a trend
towards higher MPA Ctrough during bacterial, fungal
and viral infections.[155] The relative risk of develop-
ing infections and leukopenia increased more than
Enzyme immunoassay.
Ciclosporin co-therapy.

Tacrolimus co-therapy.
Liquid chromography.

3-fold above an MPA Ctrough of 3–4 mg/L. An MPA

Ctrough upper limit of 3.5 mg/L was suggested. In a
Median (range).
Incidence (%).
No AEs

retrospective study of 30 renal transplant patients,

Table VII. Contd
Event

the mean MPA Ctrough was significantly higher in

AUC9.

individuals who experienced adverse effects com-

patients

pared with those who did not.[174] Thirteen patients

No. of

developed adverse effects including cytome-

a
b

d
e

g
h
c

k
f

i
j

© 2007 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2007; 46 (1)
48
galovirus infection (n = 3), pneumonia (n = 3),
urinary tract infection (n = 3), herpes zoster (n = 1),
infected haematoma (n = 1), pancreatitis (n = 1) and
leukopenia (n = 1). Similarly, the median MPA
Ctrough was significantly higher in patients with
toxicity in a prospective study of 15 stable renal
transplant patients.[171] Subjects were switched from
ciclosporin to mycophenolate mofetil 1 year after
transplantation. Adverse effects occurred in seven
patients and included hair loss (n = 2), anaemia (n =
4) or both (n = 1). In a study of 22 Chinese kidney
transplant recipients, MPA Ctrough was significantly
higher in patients who experienced infection,
haematological adverse effects and diarrhoea than in
those who did not experience these events or acute
rejection.[159] Although correlations between Ctrough
and clinical events were significant, the relation-
ships did not have a high degree of sensitivity or
specificity.[159] Subjects were followed up for 6
months.
Free MPA exposure may provide greater predic-
tive value than total MPA AUC or Ctrough as a risk
factor for leukopenia (table VIII).[28,32,96,175] In one
case report, a patient with severe nausea, vomiting,
haematemesis and pancytopenia was found to have
markedly elevated free MPA AUC6 (2.3 mg • h/L)
and free MPA fraction (18.3%).[96] In a study of 42
renal transplant recipients, free MPA AUC6 was
significantly higher in 14 patients who experienced
thrombocytopenia, leukopenia and/or infectious
complications.[32] Free MPA AUC6 was measured
on day 5 and related to adverse effects in the first
month post-transplant.[32] In an open-label longitudi-
nal study involving 45 paediatric kidney recipients,
free MPA AUC12 was able to discriminate individu-
als with and without infections and/or leukopenia in
the first 1–3 weeks and 3–6 months post-transplant
(not shown in table VIII).[80] The cut-off in the first
1–3 weeks was a free MPA AUC12 of 0.4 mg • h/L
with a diagnostic sensitivity of 92.3% and specifici-
ty of 61.0% for infections and leukopenia.[80] Simi-
larly, percentage free MPA and free MPA Ctrough
was higher in patients with anaemia than in those
with a normal red blood cell count in a study of 46
kidney recipients 6–9 months after transplanta-
tion.[172] Total MPA Ctrough was comparable in both
groups.[172] A significant negative correlation was
also shown between percent free MPA, but not free
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
MPA Ctrough or total MPA Ctrough and leukocyte
count.[172] Finally, one prospective, 12-month, mul-
ticentre study in 33 renal transplant recipients re-
ported a relationship between high MPAG and
AcMPAG concentrations and development of leu-
kopenia and anaemia.[61]
There is no consensus in the literature regarding
the exposure measure that best correlates with the
incidence of adverse effects or infection (tables VII
and VIII). Mycophenolate mofetil gastrointestinal
toxicity appears to be dose-related.[176] Local con-
centrations of MPA in gastrointestinal epithelial
cells, not reflecting systemic exposure, may contrib-
ute to gastrointestinal irritation.[176] Haematological
disorders including leukopenia and anaemia have
been associated with high MPA AUC,[156] high
Ctrough,[155,156,159] high free drug exposure[32,80,172]
and high metabolite concentrations[61] in some, but
not all, studies.[61,160,161] The difficulties in establish-
ing a clear-cut relationship between MPA exposure
and toxicity may be a result of differences in renal
function and pharmacokinetics of MPA metabolites
between patients and the fact that such relationships
are time-dependant.[111] Further research is required
in this area before specific recommendations to pre-
vent adverse effects of mycophenolate can be made.
It appears, from data summarised in table VII, that
an MPA AUC12 above 60 mg • h/L may increase the
risk of toxicity.
8. Target Concentration Intervention
There are several reasons to consider individual-
isation of mycophenolate treatment in preference to
giving a standard dosage, including: (i) large BSV in
the pharmacokinetics (tables I and II) and pharma-
codynamics of mycophenolate; (ii) a definite rela-
tionship between efficacy and exposure and a possi-
ble separation of effective and toxic exposure (tables
VI and VII); and (iii) the large number of factors
known to influence the pharmacokinetics of
mycophenolate. While the pharmaceutical industry
and regulatory authorities have not yet endorsed
MPA target concentration intervention (TCI), scien-
tific societies and consensus conferences have made
such recommendations.[170,177,178] TCI may be par-
ticularly useful in the first 2 months post-transplant,
prior to major changes in anti-rejection therapy
(such as corticosteroid withdrawal and tapering of
Clin Pharmacokinet 2007; 46 (1)
 Table VIII. Summary of pharmacodynamic studies of mycophenolate mofetil involving metabolites and free drug measurement in adult kidney transplant recipients
No. of Event (no. Time post- MPAG Ctrough AcMPAG Free MPA Free fraction AcMPAG/ Comments Reference
patients of patients) transplant (mg/L)a Ctrough Ctrough (mg/L)a (%)a,b MPA ratio
(mg/L)a
33c,d No rejection (4)e ≤1y 56.6 0.12 0.05 Difference in tacrolimus 61
Rejection (4)e 78.0 0.36 0.11 Ctrough at times patients
No diarrhoea (4)e 58.6 0.09 50.4 0.05 did and did not have
Diarrhoea (4)e 65.5 0.16 72.6 0.08 anaemia
No leukopenia (10)e 60.5 0.17 35.4 0.10
Leukopenia (10)e 47.2f 0.18 34.2 0.10
e
No anaemia (19) 58.3 0.12 27.9 0.06
Anemia (19)e 62.8,f 0.24f 34.2 0.10f
38d,g No rejection (22) ≤10mo 0.81 ± 0.25 No difference in 70

© 2007 Adis Data Information BV. All rights reserved.

Rejection grade 1 (13) 0.95 ± 0.34 ciclosporin Ctrough
Rejection grade 2/3 (3) 0.49 ± 0.11f between groups
42c,d,g Rejection (7) ≥1mo 1.4 (1.3–2.1)h,i No difference in 32
No rejection (35) 0.9 (0.6–1.5)h,i calcineurin Ctrough
between groups
PK and PD of Mycophenolate in Solid Organ Transplantation

46d,g No anaemia 6–9mo 30 ± 22 1.63 ± 0.88 No difference in 172

Anemia 64 ± 25f 2.31 ± 0.71f ciclosporin dose, Ctrough
or AUC between groups
42c,d,g Haematogical AEs (9) ≥1mo 1.9 ± 0.3f,h Difference in ciclosporin 32
No haematological AEs (33) 1.1 ± 0.1h and tacrolimus Ctrough
between groups not
examined
a Values are expressed as mean ± SD unless specified otherwise.
b Percentage free/total.
c Tacrolimus co-therapy.
d Liquid chromatography.
e Intra-individual patient differences.
f Statistically significantly different compared with no rejection or rejection grade 1 or no AEs group.
g Ciclosporin co-therapy.
h AUC6 (mg • h/L).
i Median (range).
AcMPAG = acyl-glucuronide MPAG; AE = adverse effect; AUC = area under the concentration-time curve; AUC6 = AUC from 0 to 6 hours; Ctrough = trough concentration; MPA =
mycophenolic acid; MPAG = 7-O-MPA-glucuronide.

Clin Pharmacokinet 2007; 46 (1)

49
50
other immunosuppressant doses), and at the time of
major clinical events, such as rejection or infec-
tion.[179] In patients with impaired renal or liver
function and hypoalbuminemia, measurement of
free drug, in addition to total MPA concentration,
may be valuable in further interpretation of MPA
exposure.[2,25,32]
MPA AUC12 is likely to be the most useful
exposure measure early post-transplant. Elements in
favour of MPA AUC rather than Ctrough based TCI
are a stronger pharmacokinetic-pharmacodynamic
relationship between acute rejection and AUC12
than Ctrough, and lower BOV in AUC12 compared
with Ctrough.[110,180] It would appear reasonable to
target a total MPA AUC12 of 30–60 mg • hr/L in
patients without hypoalbuminemia or without se-
verely impaired renal or hepatic function. This is
likely to minimise the risk of rejection and may
reduce the risk of toxicity. Possibly, in stable trans-
plant recipients, Ctrough may suffice. However, it is
not possible at this stage to recommend a target
range for Ctrough.
Several assay methods have been developed for
MPA concentration measurement including HPLC,
HPLC with mass spectrometric detection and EMIT
assay.[29,181] HPLC-based methods have also been
adapted to measure MPAG and AcMPAG.[182,183] In
addition, concurrent free and total MPA measure-
ment is possible.[184,185] MPA concentrations mea-
sured by EMIT are generally higher than those mea-
sured by HPLC-based methods, with variation de-
pending on the transplant population, post-
transplant period and sampling time.[152,186,187] The
MPA antibody used in the EMIT assay cross-reacts
with AcMPAG; overestimation is between 5% and
40%.[152,187,188] As AcMPAG is pharmacologically
activity in vitro, it has been speculated that EMIT
measurement during mycophenolate treatment may
better reflect immunosuppression than HPLC tech-
niques that only measure the parent compound.[110]
However, there remains uncertainty regarding all of
the factors that contribute to the bias of the EMIT
methods, and validated HPLC methods provide the
most accurate assessment of the primary active com-
pound, MPA.[29]
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
9. Estimation of Mycophenolic Acid
Area Under the Concentration-Time
Curve from 0 to 12 Hours
A number of limited sampling strategies to esti-
mate MPA AUC12, without measuring the full con-
centration-time profile, have been published.[189-193]
These generally involve MPA measurement in the
first 6 hours post-dose, with employment of an
algorithm to predict the full AUC12. In some studies,
a 2-hour abbreviated AUC, often obtained with
three sampling points (pre-dose, 30 or 40 minutes,
and 2 hours post-dose), has been suggest-
ed.[189,192,193] However, abbreviated sampling strate-
gies <6–8 hours post-dose are likely to miss MPA
enterohepatic recycling, which is especially impor-
tant in patients receiving concomitant tacrolimus or
sirolimus therapy. Furthermore, all limited sampling
strategies require strict adherence to the time of
blood sample collection.
Another possible method for AUC12 estimation
based on taking only a few concentration-time mea-
surements is use of a maximum a posteriori (MAP)
Bayesian procedure. During Bayesian dosage pre-
diction, pharmacokinetic parameters are estimated
for each individual, based on previous population
data available for the drug and sparse concentration-
time measurements from that patient. One advan-
tage of MAP Bayesian forecasting over algorithm
extrapolation is flexibility in blood sample timing
(as long as the correct sample and dose times are
known). Bayesian estimation nevertheless involves
more complex calculation and requires a pre-ex-
isting population pharmacokinetic model.
To date, two studies have used MAP Bayesian
procedures for estimation of MPA AUC12.[104,194]
Individual estimates of MPA AUC were obtained
with satisfactory accuracy (bias 7.7%, range of pre-
dicted error 0.43–15.1%) and precision (root mean
squared error 12.4%) in a study of 10 stable adult
kidney recipients at least 6 months post-trans-
plant.[104] MPA concentrations measured at 20 min-
utes, 1 and 3 hours post-dose, along with patient
bodyweight, were used for Bayesian estimation and
then compared with a full MPA concentration-time
profile obtained using extra samples drawn at 0, 40
minutes, 1.5, 2, 4, 6 and 9 hours.[104] The population
model employed was developed independently and
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
based on 60 stable renal transplant recipients (see
section 6).[104] Bayesian estimation of MPA AUC,
based on three concentration-time measurements
per individual, was also satisfactory in a retrospec-
tive study of 44 adult kidney transplant recipi-
ents.[194] Bayesian estimates were compared with
AUC estimates obtained through full concentration-
time profiling.[194] Bayesian AUC was estimated
with an absolute bias >20% in 39.7% of patients on
day 7 post-transplant, 16.7% on day 30 post-trans-
plant and only 10% at 3 months post-transplant.[194]
Imprecision (root mean squared error) associated
with Bayesian estimation ranged from 20% (day 7)
to 12% (>3 months).[194] One criticism of this study
is that the population model employed in Bayesian
prediction was developed on these same 44 patients,
rather than in an independent sample.[194]
10. Pharmacodynamic Monitoring
Pharmacodynamic monitoring by measurement
of IMPDH activity is a novel approach to individu-
alisation of mycophenolate therapy, as it may better
reflect biological response to the drug.[195] To date,
measurement of IMPDH activity is not available as
an alternative to monitoring as it is a complex analy-
sis; however, it is starting to be investigated in
research studies. Assays of IMPDH activity are
technically demanding and, to date, the results have
been somewhat difficult to interpret.[196]
Initially, using whole blood assays, an unexpect-
ed increase in IMPDH activity and guanosine
triphosphate nucleotide (GTP) levels was reported
in patients after prolonged mycophenolate mofetil
therapy.[197,198] However, whole blood measurement
of IMPDH activity is unlikely to reflect its activity
in lymphocytes.[199] More recent studies have
demonstrated that mycophenolate mofetil signifi-
cantly reduces IMPDH and GTP levels in isolated
peripheral blood mononuclear cells
(PBMCs).[200,201] PBMCs are likely to be the pre-
ferred matrix for measurement of IMPDH activi-
ty.[199]
A validated HPLC method has been developed
that measures the rate of xanthine monophosphate
production by PBMCs under controlled in vitro
conditions.[202] A relationship between post-trans-
plant pre-dose IMPDH activity and corresponding
MPA plasma concentrations has been reported in 35
© 2007 Adis Data Information BV. All rights reserved.
51
patients (58 determinates) with a coefficient of de-
termination (r2) of 0.235.[203] Large differences in
IMPDH activity prior to transplantation have been
reported.[203] Correlations have also been found be-
tween pre-operative IMPDH results and post-trans-
plant outcome.[203] In one analysis, 48 renal trans-
plant recipients patients who required a mycopheno-
late mofetil dose reduction due to adverse effects
during follow-up had significantly lower pre-trans-
plant IMPDH activity compared with patients who
did not.[203] One study has also used a real-time
polymerase chain reaction technique to quantitively
assess IMPDH2 gene expression in liver transplant
recipients.[204] Wide inter-individual variability in
expression was reported, with a trend to a higher
level of IMPDH2 expression in patients with treat-
ment-related toxicities.
Considerable inter-individual variability in
IMPDH activity, with relatively small intra-individ-
ual variability, makes monitoring of this pharmaco-
dynamic parameter attractive.[196] However, many
questions are yet to be answered.[196] The causes of
large between-subject variability in IMPDH activity
pre-transplant needs to be investigated. It is not
known whether IMPDH activity increases prior to
rejection or if other promotors of lymphocyte activa-
tion, such as infection, also induce IMPDH activity.
Experimentation is needed into whether differences
in IMPDH activity predict efficacy and dose re-
quirements of mycophenolate mofetil, and how dif-
ferences in free MPA concentration may affect
IMPDH activity. Post-transplant IMPDH activity
while on mycophenolate therapy needs to be related
to outcome. Prospective trials following patients
longitudinally should be an important source of use-
ful new data.[196]
11. Conclusions
Ten years after the introduction of mycopheno-
late into the clinical arena, it is timely to review the
pharmacokinetic and pharmacodynamic data availa-
ble on this immunosuppressant. There has been
heightened interest in individualisation of mycophe-
nolate dosing as a means of improving the good
clinical results already obtained with this drug. This
goal could be achieved by TCI (aiming for an MPA
AUC12 of 30–60 mg • h/L) using Bayesian forecast-
ing and considering patient demographic and
Clin Pharmacokinet 2007; 46 (1)
52
clinical factors that influence the pharmacokinetics
of MPA. Ultimately, by adjusting the mycopheno-
late dosage based on exposure (AUC12) and consid-
ering factors such as concomitant immunosuppres-
sion, serum albumin, renal function and possibly
UGT genotype, it may become possible to improve
patient clinical outcome. A large multicentre study
in renal transplantation has recently commenced,
examining the clinical relevance of concentration-
controlled mycophenolate mofetil dose adjustments
based on abbreviated (2-hour) target AUC profiles
versus fixed dose treatment.[205] Whether AUC mon-
itoring of mycophenolate is advantageous, in terms
of both improving efficacy and reducing toxicity,
will be assessed. Additional investigation is required
in several areas including: (i) the influence of im-
paired hepatic function on MPA pharmacokinetics;
(ii) pharmacokinetic mechanisms such as
glucuronidation, active biliary and renal tubular se-
cretion and enterohepatic re-absorption, and any
influence of pharmacogenetics on these processes;
(iii) the relationship between MPA exposure mea-
sures and drug toxicity; (iv) the relationship between
MPA metabolites and toxicity; (v) the development
of population models in larger and more diverse
transplant populations; (vi) further testing of the
utility of Bayesian forecasting; and (vii) further ex-
amination of pharmacodynamic monitoring through
IMPDH measurement.
Acknowledgements
Dr Staatz would like to acknowledge financial support
from an Australian National Health and Medical Research
Council Neil Hamilton Fairley Fellowship. The authors have
no pharmaceutical industry affiliation and have no pecuniary
interests (personal or professional), grants or other potential
conflicts of interest with any pharmaceutical company that
are directly relevant to the content of this review.
References
1. Kaufman DB, Shapiro R, Lucey MR, et al. Immunosuppression:
practice and trends. Am J Transplant 2004; 4 Suppl. 9: 38-53
2. Shaw LM, Nawrocki A, Korecka M, et al. Using established
immunosuppressant therapy effectively: lessons from the mea-
surement of mycophenolic acid plasma concentrations. Ther
Drug Monit 2004; 26 (4): 347-51
3. Roche Pharmaceuticals. CellCept®: complete product informa-
tion [online]. Available from URL: http://www.rocheusa.com/
products/cellcept [Accessed 2006 Dec 7]
4. European Mycophenolate Mofetil Cooperative Study Group.
Placebo-controlled study of mycophenolate mofetil combined
with cyclosporin and corticosteroids for prevention of acute
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
rejection. European Mycophenolate Mofetil Cooperative
Study Group. Lancet 1995; 345 (8961): 1321-5
5. The Tricontinental Mycophenolate Mofetil Renal Transplanta-
tion Study Group. A blinded, randomized clinical trial of
mycophenolate mofetil for the prevention of acute rejection in
cadaveric renal transplantation. The Tricontinental Mycophe-
nolate Mofetil Renal Transplantation Study Group. Transplan-
tation 1996; 61 (7): 1029-37
6. Sollinger HW, for the US Renal Transplant Mycophenolate
Mofetil Study Group. Mycophenolate mofetil for the preven-
tion of acute rejection in primary cadaveric renal allograft
recipients. Transplantation 1995; 60 (3): 225-32
7. Novartis Pharmaceuticals Corporation. Myfortic®: prescribing
information [online]. Available from URL: http://
www.pharma.us.novartis.com/product/pi/pdf/myfortic.pdf
[Accessed 2006 Dec 7]
8. Granger DK. Enteric-coated mycophenolate sodium: results of
two pivotal global multicenter trials. Transplant Proc 2001; 33
(7-8): 3241-4
9. Salvadori M, Holzer H, de Mattos A, et al. Enteric-coated
mycophenolate sodium is therapeutically equivalent to
mycophenolate mofetil in de novo renal transplant patients.
Am J Transplant 2004; 4 (2): 231-6
10. Allison AC. Mechanisms of action of mycophenolate mofetil.
Lupus 2005; 14 Suppl. 1: s2-8
11. Halloran P, Mathew T, Tomlanovich S, et al. Mycophenolate
mofetil in renal allograft recipients: a pooled efficacy analysis
of three randomized, double-blind, clinical studies in preven-
tion of rejection. The International Mycophenolate Mofetil
Renal Transplant Study Groups. Transplantation 1997; 63 (1):
39-47
12. Lee WA, Gu L, Miksztal AR, et al. Bioavailability improvement
of mycophenolic acid through amino ester derivatization.
Pharm Res 1990; 7 (2): 161-6
13. Bullingham R, Monroe S, Nicholls A, et al. Pharmacokinetics
and bioavailability of mycophenolate mofetil in healthy sub-
jects after single-dose oral and intravenous administration. J
Clin Pharmacol 1996; 36 (4): 315-24
14. Armstrong VW, Tenderich G, Shipkova M, et al.
Pharmacokinetics and bioavailability of mycophenolic acid
after intravenous administration and oral administration of
mycophenolate mofetil to heart transplant recipients. Ther
Drug Monit 2005; 27 (3): 315-21
15. Bullingham RE, Nicholls AJ, Kamm BR. Clinical
pharmacokinetics of mycophenolate mofetil. Clin
Pharmacokinet 1998; 34 (6): 429-55
16. Arns W, Breuer S, Choudhury S, et al. Enteric-coated mycophe-
nolate sodium delivers bioequivalent MPA exposure compared
with mycophenolate mofetil. Clin Transplant 2005; 19 (2):
199-206
17. Pescovitz MD, Conti D, Dunn J, et al. Intravenous mycopheno-
late mofetil: safety, tolerability, and pharmacokinetics. Clin
Transplant 2000; 14 (3): 179-88
18. Braun KP, Glander P, Hambach P, et al. Pharmacokinetics and
pharmacodynamics of mycophenolate mofetil under oral and
intravenous therapy. Transplant Proc 2002; 34 (5): 1745-7
19. Nowak I, Shaw LM. Mycophenolic acid binding to human
serum albumin: characterization and relation to pharmacody-
namics. Clin Chem 1995; 41 (7): 1011-7
20. Langman LJ, LeGatt DF, Yatscoff RW. Blood distribution of
mycophenolic acid. Ther Drug Monit 1994; 16 (6): 602-7
21. Bullingham RE, Nicholls A, Hale M. Pharmacokinetics of
mycophenolate mofetil (RS61443): a short review. Transplant
Proc 1996; 28 (2): 925-9
22. Weber LT, Shipkova M, Lamersdorf T, et al. Pharmacokinetics
of mycophenolic acid (MPA) and determinants of MPA free
fraction in pediatric and adult renal transplant recipients. Ger-
man Study group on Mycophenolate Mofetil Therapy in Pedi-
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
atric Renal Transplant Recipients. J Am Soc Nephrol 1998; 9
(8): 1511-20
23. Ensom MH, Partovi N, Decarie D, et al. Pharmacokinetics and
protein binding of mycophenolic acid in stable lung transplant
recipients. Ther Drug Monit 2002; 24 (2): 310-4
24. Nowak I, Shaw LM. Effect of mycophenolic acid glucuronide
on inosine monophosphate dehydrogenase activity. Ther Drug
Monit 1997; 19 (3): 358-60
25. Atcheson BA, Taylor PJ, Kirkpatrick CM, et al. Free mycophe-
nolic acid should be monitored in renal transplant recipients
with hypoalbuminemia. Ther Drug Monit 2004; 26 (3): 284-6
26. Kaplan B, Meier-Kriesche HU, Friedman G, et al. The effect of
renal insufficiency on mycophenolic acid protein binding. J
Clin Pharmacol 1999; 39 (7): 715-20
27. Shaw LM, Mick R, Nowak I, et al. Pharmacokinetics of
mycophenolic acid in renal transplant patients with delayed
graft function. J Clin Pharmacol 1998; 38 (3): 268-75
28. Meier-Kriesche HU, Shaw LM, Korecka M, et al.
Pharmacokinetics of mycophenolic acid in renal insufficiency.
Ther Drug Monit 2000; 22 (1): 27-30
29. Shaw LM, Holt DW, Oellerich M, et al. Current issues in
therapeutic drug monitoring of mycophenolic acid: report of a
roundtable discussion. Ther Drug Monit 2001; 23 (4): 305-15
30. Shaw LM, Korecka M, DeNofrio D, et al. Pharmacokinetic,
pharmacodynamic, and outcome investigations as the basis for
mycophenolic acid therapeutic drug monitoring in renal and
heart transplant patients. Clin Biochem 2001; 34 (1): 17-22
31. Venkataramanan R, Ou J, Pisupati J, et al. Does plasma protein
binding of mycophenolic acid affect its clearance? Fifth Con-
gress of the International Liver Transplantation Society; 1999
Aug 26-29; Pittsburgh (PA)
32. Atcheson BA, Taylor PJ, Mudge DW, et al. Mycophenolic acid
pharmacokinetics and related outcomes early after renal trans-
plant. Br J Clin Pharmacol 2005; 59 (3): 271-80
33. Picard N, Ratanasavanh D, Premaud A, et al. Identification of
the UDP-glucuronosyltransferase isoforms involved in
mycophenolic acid phase II metabolism. Drug Metab Dispos
2005; 33 (1): 139-46
34. Bowalgaha K, Miners JO. The glucuronidation of mycophenolic
acid by human liver, kidney and jejunum microsomes. Br J
Clin Pharmacol 2001; 52 (5): 605-9
35. Shipkova M, Armstrong VW, Wieland E, et al. Identification of
glucoside and carboxyl-linked glucuronide conjugates of
mycophenolic acid in plasma of transplant recipients treated
with mycophenolate mofetil. Br J Pharmacol 1999; 126 (5):
1075-82
36. Schutz E, Shipkova M, Armstrong VW, et al. Identification of a
pharmacologically active metabolite of mycophenolic acid in
plasma of transplant recipients treated with mycophenolate
mofetil. Clin Chem 1999; 45 (3): 419-22
37. Shipkova M, Strassburg CP, Braun F, et al. Glucuronide and
glucoside conjugation of mycophenolic acid by human liver,
kidney and intestinal microsomes. Br J Pharmacol 2001; 132
(5): 1027-34
38. Shipkova M, Schutz E, Armstrong VW, et al. Determination of
the acyl glucuronide metabolite of mycophenolic acid in
human plasma by HPLC and Emit. Clin Chem 2000; 46 (3):
365-72
39. Shipkova M, Armstrong VW, Oellerich M, et al. Acyl glucuro-
nide drug metabolites: toxicological and analytical implica-
tions. Ther Drug Monit 2003; 25 (1): 1-16
40. Wieland E, Shipkora M, Schutz E, et al. The acyl gluronide of
the immunosuppressant mycophenolic acid induces release of
proinflammatory cytockines and TNF-alpha mRNA expres-
sion [abstract]. Clin Clem 1999; 45 Suppl. 6: A127
41. Wieland E, Shipkova M, Schellhaas U, et al. Induction of
cytokine release by the acyl glucuronide of mycophenolic acid:
a link to side effects? Clin Biochem 2000; 33 (2): 107-13
© 2007 Adis Data Information BV. All rights reserved.
53
42. Maes BD, Dalle I, Geboes K, et al. Erosive enterocolitis in
mycophenolate mofetil-treated renal-transplant recipients with
persistent afebrile diarrhea. Transplantation 2003; 75 (5):
665-72
43. Basu NK, Kole L, Kubota S, et al. Human UDP-glucuronosyl-
transferases show atypical metabolism of mycophenolic acid
and inhibition by curcumin. Drug Metab Dispos 2004; 32 (7):
768-73
44. Bernard O, Guillemette C. The main role of UGT1A9 in the
hepatic metabolism of mycophenolic acid and the effects of
naturally occurring variants. Drug Metab Dispos 2004; 32 (8):
775-8
45. Picard N, Cresteil T, Premaud A, et al. Characterization of a
phase 1 metabolite of mycophenolic acid produced by
CYP3A4/5. Ther Drug Monit 2004; 26 (6): 600-8
46. Kuypers DR, Naesens M, Vermeire S, et al. The impact of
uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9)
gene promoter region single-nucleotide polymorphisms
T-275A and C-2152T on early mycophenolic acid dose-inter-
val exposure in de novo renal allograft recipients. Clin
Pharmacol Ther 2005; 78 (4): 351-61
47. Hesselink DA, van Gelder T. Genetic and nongenetic determi-
nants of between-patient variability in the pharmacokinetics of
mycophenolic acid. Clin Pharmacol Ther 2005; 78 (4): 317-21
48. Kobayashi M, Saitoh H, Tadano K, et al. Cyclosporin A, but not
tacrolimus, inhibits the biliary excretion of mycophenolic acid
glucuronide possibly mediated by multidrug resistance-associ-
ated protein 2 in rats. J Pharmacol Exp Ther 2004; 309 (3):
1029-35
49. Naderer OJ, Dupuis RE, Heinzen EL, et al. The influence of
norfloxacin and metronidazole on the disposition of mycophe-
nolate mofetil. J Clin Pharmacol 2005; 45 (2): 219-26
50. Wollenberg K, Krumme B, Pisarski P, et al. Pharmacokinetics
of mycophenolic acid in the early period after kidney trans-
plantation. Transplant Proc 1998; 30 (8): 4090-1
51. Wollenberg K, Krumme B, Schollmeyer P, et al.
Pharmacokinetics of mycophenolic acid after renal transplan-
tation. Transplant Proc 1998; 30 (5): 2237-9
52. Liang MZ, Lu YP, Nan F, et al. Pharmacokinetics of mycophe-
nolic acid after a single and multiple oral doses of mycopheno-
late mofetil in Chinese renal transplant recipients. Transplant
Proc 2004; 36 (7): 2065-7
53. Jirasiritham S, Sumethkul V, Mavichak V, et al. The
pharmacokinetics of mycophenolate mofetil in Thai kidney
transplant recipients. Transplant Proc 2004; 36 (7): 2076-8
54. Undre NA, van Hooff J, Christiaans M, et al. Pharmacokinetics
of FK 506 and mycophenolic acid after the administration of a
FK 506-based regimen in combination with mycophenolate
mofetil in kidney transplantation. Transplant Proc 1998; 30
(4): 1299-302
55. Yeung S, Tong KL, Tsang WK, et al. Pharmacokinetic study of
mycophenolate mofetil in Asian renal transplant recipients.
Transplant Proc 2000; 32 (7): 1753-4
56. Cho EK, Han DJ, Kim SC, et al. Pharmacokinetic study of
mycophenolic acid in Korean kidney transplant patients. J Clin
Pharmacol 2004; 44 (7): 743-50
57. Engelbertink R, Smak Gregoor P, Hesse C, et al. High
mycophenolic acid area under-the-curve values in renal trans-
plant recipients on long-term mycophenolate mofetil treat-
ment. Transplant Proc 2002; 34 (7): 2983-4
58. Brunet M, Martorell J, Oppenheimer F, et al. Pharmacokinetics
and pharmacodynamics of mycophenolic acid in stable renal
transplant recipients treated with low doses of mycophenolate
mofetil. Transpl Int 2000; 13 Suppl. 1: S301-5
59. Neumann I, Haidinger M, Jager H, et al. Pharmacokinetics of
mycophenolate mofetil in patients with autoimmune diseases
compared renal transplant recipients. J Am Soc Nephrol 2003;
14 (3): 721-7
Clin Pharmacokinet 2007; 46 (1)
54
60. Mourad M, Malaise J, Chaib Eddour D, et al. Correlation of
mycophenolic acid pharmacokinetic parameters with side ef-
fects in kidney transplant patients treated with mycophenolate
mofetil. Clin Chem 2001; 47 (1): 88-94
61. Kuypers DR, Vanrenterghem Y, Squifflet JP, et al. Twelve-
month evaluation of the clinical pharmacokinetics of total and
free mycophenolic acid and its glucuronide metabolites in
renal allograft recipients on low dose tacrolimus in combina-
tion with mycophenolate mofetil. Ther Drug Monit 2003; 25
(5): 609-22
62. Satoh S, Tada H, Murakami M, et al. The influence of mycophe-
nolate mofetil versus azathioprine and mycophenolic acid
pharmacokinetics on the incidence of acute rejection and infec-
tious complications after renal transplantation. Transplant Proc
2005; 37 (4): 1751-3
63. Johnson AG, Rigby RJ, Taylor PJ, et al. The kinetics of
mycophenolic acid and its glucuronide metabolite in adult
kidney transplant recipients. Clin Pharmacol Ther 1999; 66
(5): 492-500
64. Tedesco-Silva H, Bastien MC, Choi L, et al. Mycophenolic acid
metabolite profile in renal transplant patients receiving enteric-
coated mycophenolate sodium or mycophenolate mofetil.
Transplant Proc 2005; 37 (2): 852-5
65. Budde K, Glander P, Hahn U, et al. Pharmacokinetics and
pharmacodynamic comparison of mycophenolate mofetil and
enteric-coated mycophenolate sodium in maintenance renal
transplant patients [abstract no. 1036]. Am J Transplant 2002;
2002 (2 Suppl. 3): 399
66. Sumethkul V, Na-Bangchang K, Kantachuvesiri S, et al. Stan-
dard dose enteric-coated mycophenolate sodium (myfortic)
delivers rapid therapeutic mycophenolic acid exposure in kid-
ney transplant recipients. Transplant Proc 2005; 37 (2): 861-3
67. Gabardi S, Tran JL, Clarkson MR. Enteric-coated mycopheno-
late sodium. Ann Pharmacother 2003; 37 (11): 1685-93
68. Pisupati J, Jain A, Burckart G, et al. Intraindividual and inter-
individual variations in the pharmacokinetics of mycophenolic
acid in liver transplant patients. J Clin Pharmacol 2005; 45 (1):
34-41
69. Jain A, Venkataramanan R, Hamad IS, et al. Pharmacokinetics
of mycophenolic acid after mycophenolate mofetil administra-
tion in liver transplant patients treated with tacrolimus. J Clin
Pharmacol 2001; 41 (3): 268-76
70. DeNofrio D, Loh E, Kao A, et al. Mycophenolic acid concentra-
tions are associated with cardiac allograft rejection. J Heart
Lung Transplant 2000; 19 (11): 1071-6
71. Ensom MH, Partovi N, Decarie D, et al. Mycophenolate
pharmacokinetics in early period following lung or heart trans-
plantation. Ann Pharmacother 2003; 37 (12): 1761-7
72. Jacqz-Aigrain E, Khan Shaghaghi E, Baudouin V, et al.
Pharmacokinetics and tolerance of mycophenolate mofetil in
renal transplant children. Pediatr Nephrol 2000; 14 (2): 95-9
73. Sherbotie J, Bunchman T, Navarra P. Mycophenolate mofetil
(MMF) oral suspension in pediatric renal transplantation [ab-
stract; online]. American Society of Transplantation 18th An-
nual Meeting; 1999 May 15-19; Chicago (IL). Available from
URL: http://www.a-s-t.org/library/abstracts99/473.htm [Ac-
cessed 2006 Dec 14]
74. Weber LT, Lamersdorf T, Shipkova M, et al. Area under the
plasma concentration-time curve for total, but not for free,
mycophenolic acid increases in the stable phase after renal
transplantation: a longitudinal study in pediatric patients. Ger-
man Study Group on Mycophenolate Mofetil Therapy in Pedi-
atric Renal Transplant Recipients. Ther Drug Monit 1999; 21
(5): 498-506
75. Filler G, Lampe D, Mai I, et al. Dosing of MMF in combination
with tacrolimus for steroid-resistant vascular rejection in pedi-
atric renal allografts. Transpl Int 1998; 11 Suppl. 1: S82-5
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
76. Weber LT, Schutz E, Lamersdorf T, et al. Pharmacokinetics of
mycophenolic acid (MPA) and free MPA in paediatric renal
transplant recipients: a multicentre study. The German Study
Group on Mycophenolate Mofetil (MMF) Therapy. Nephrol
Dial Transplant 1999; 14 Suppl. 4: 33-4
77. Filler G, Lepage N, Delisle B, et al. Effect of cyclosporine on
mycophenolic acid area under the concentration-time curve in
pediatric kidney transplant recipients. Ther Drug Monit 2001;
23 (5): 514-9
78. Armstrong VW, Shipkova M, Schutz E, et al. Monitoring of
mycophenolic acid in pediatric renal transplant recipients.
Transplant Proc 2001; 33 (1-2): 1040-3
79. Ghio L, Ferraresso M, Vigano SM, et al. Mycophenolate mofetil
pharmacokinetic monitoring in pediatric kidney transplant re-
cipients. Transplant Proc 2005; 37 (2): 856-8
80. Weber LT, Shipkova M, Armstrong VW, et al. The
pharmacokinetic-pharmacodynamic relationship for total and
free mycophenolic acid in pediatric renal transplant recipients:
a report of the German Study Group on Mycophenolate Mofe-
til Therapy. J Am Soc Nephrol 2002; 13 (3): 759-68
81. Aigrain EJ, Shaghaghi EK, Baudouin V, et al. Pharmacokinetics
of mycophenolate mofetil in eight pediatric renal transplant
patients. Transplant Proc 2000; 32 (2): 388-90
82. Shipkova M, Armstrong VW, Weber L, et al. Pharmacokinetics
and protein adduct formation of the pharmacologically active
acyl glucuronide metabolite of mycophenolic acid in pediatric
renal transplant recipients. Ther Drug Monit 2002; 24 (3):
390-9
83. Bunchman T, Navarro M, Broyer M, et al. The use of mycophe-
nolate mofetil suspension in paediatric renal allograft recipi-
ents. Pediatric Nephrol 2001; 16: 978-84
84. Pescovitz MD, Bumgardner G, Gaston RS, et al.
Pharmacokinetics of daclizumab and mycophenolate mofetil
with cyclosporine and steroids in renal transplantation. Clin
Transplant 2003; 17 (6): 511-7
85. Brown NW, Aw MM, Mieli-Vergani G, et al. Mycophenolic
acid and mycophenolic acid glucuronide pharmacokinetics in
pediatric liver transplant recipients: effect of cyclosporine and
tacrolimus comedication. Ther Drug Monit 2002; 24 (5):
598-606
86. Sollinger HW, Deierhoi MH, Belzer FO, et al. RS-61443: a
phase I clinical trial and pilot rescue study. Transplantation
1992; 53 (2): 428-32
87. Behrend M, Braun F. Enteric-coated mycophenolate sodium:
tolerability profile compared with mycophenolate mofetil.
Drugs 2005; 65 (8): 1037-50
88. Ettenger R, Bartosh S, Choi L, et al. Pharmacokinetics of
enteric-coated mycophenolate sodium in stable pediatric renal
transplant recipients. Pediatr Transplant 2005; 9 (6): 780-7
89. Holt DW. Monitoring mycophenolic acid. Ann Clin Biochem
2002; 39 (Pt 3): 173-83
90. Shum B, Duffull SB, Taylor PJ, et al. Population
pharmacokinetic analysis of mycophenolic acid in renal trans-
plant recipients following oral administration of mycopheno-
late mofetil. Br J Clin Pharmacol 2003; 56 (2): 188-97
91. Shaw LM, Korecka M, van Breeman R, et al. Analysis,
pharmacokinetics and therapeutic drug monitoring of
mycophenolic acid. Clin Biochem 1998; 31 (5): 323-8
92. Shaw LM, Kaplan B, DeNofrio D, et al. Pharmacokinetics and
concentration-control investigations of mycophenolic acid in
adults after transplantation. Ther Drug Monit 2000; 22 (1):
14-9
93. Staatz CE, Duffull SB, Kiberd B, et al. Population
pharmacokinetics of mycophenolic acid during the first week
after renal transplantation. Eur J Clin Pharmacol 2005; 61 (7):
507-16
94. Johnson HJ, Swan SK, Heim-Duthoy KL, et al. The
pharmacokinetics of a single oral dose of mycophenolate
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
mofetil in patients with varying degrees of renal function. Clin
Pharmacol Ther 1998; 63 (5): 512-8
95. Shaw LM, Korecka M, Aradhye S, et al. Mycophenolic acid
area under the curve values in African American and Cauca-
sian renal transplant patients are comparable. J Clin Pharmacol
2000; 40 (6): 624-33
96. Mudge DW, Atcheson BA, Taylor PJ, et al. Severe toxicity
associated with a markedly elevated mycophenolic acid free
fraction in a renal transplant recipient. Ther Drug Monit 2004;
26 (4): 453-5
97. Parker G, Bullingham R, Kamm B, et al. Pharmacokinetics of
oral mycophenolate mofetil in volunteer subjects with varying
degrees of hepatic oxidative impairment. J Clin Pharmacol
1996; 36 (4): 332-44
98. Jain AB, Hamad I, Zuckerman S, et al. Effect of t-tube clamping
on the pharmacokinetics of mycophenolic acid in liver trans-
plant patients on oral therapy of mycophenolate mofetil. Liver
Transpl Surg 1999; 5 (2): 101-6
99. Bullingham R, Shah J, Goldblum R, et al. Effects of food and
antacid on the pharmacokinetics of single doses of mycophe-
nolate mofetil in rheumatoid arthritis patients. Br J Clin
Pharmacol 1996; 41 (6): 513-6
100. Morgera S, Budde K, Lampe D, et al. Mycophenolate mofetil
pharmacokinetics in renal transplant recipients on peritoneal
dialysis. Transpl Int 1998; 11 (1): 53-7
101. Neylan JF. Immunosuppressive therapy in high-risk transplant
patients: dose-dependent efficacy of mycophenolate mofetil in
African-American renal allograft recipients. US Renal Trans-
plant Mycophenolate Mofetil Study Group. Transplantation
1997; 64 (9): 1277-82
102. Schweitzer EJ, Yoon S, Fink J, et al. Mycophenolate mofetil
reduces the risk of acute rejection less in African-American
than in Caucasian kidney recipients. Transplantation 1998; 65
(2): 242-8
103. Pescovitz MD, Guasch A, Gaston R, et al. Equivalent
pharmacokinetics of mycophenolate mofetil in African-Amer-
ican and Caucasian male and female stable renal allograft
recipients. Am J Transplant 2003; 3 (12): 1581-6
104. Le Guellec C, Bourgoin H, Buchler M, et al. Population
pharmacokinetics and Bayesian estimation of mycophenolic
acid concentrations in stable renal transplant patients. Clin
Pharmacokinet 2004; 43 (4): 253-66
105. van Hest RM, van Gelder T, Vulto AG, et al. Population
pharmacokinetics of mycophenolic acid in renal transplant
recipients. Clin Pharmacokinet 2005; 44 (10): 1083-96
106. Morissette P, Albert C, Busque S, et al. In vivo higher
glucuronidation of mycophenolic acid in male than in female
recipients of a cadaveric kidney allograft and under immu-
nosuppressive therapy with mycophenolate mofetil. Ther Drug
Monit 2001; 23 (5): 520-5
107. Gerbase MW, Fathi M, Spiliopoulos A, et al. Pharmacokinetics
of mycophenolic acid associated with calcineurin inhibitors:
long-term monitoring in stable lung recipients with and with-
out cystic fibrosis. J Heart Lung Transplant 2003; 22 (5):
587-90
108. van Hest RM, Mathot RA, Vulto AG, et al. Mycophenolic acid
in diabetic renal transplant recipients: pharmacokinetics and
application of a limited sampling strategy. Ther Drug Monit
2004; 26 (6): 620-5
109. Hale MD, Nicholls AJ, Bullingham RE, et al. The
pharmacokinetic-pharmacodynamic relationship for mycophe-
nolate mofetil in renal transplantation. Clin Pharmacol Ther
1998; 64 (6): 672-83
110. Oellerich M, Shipkova M, Schutz E, et al. Pharmacokinetic and
metabolic investigations of mycophenolic acid in pediatric
patients after renal transplantation: implications for therapeutic
drug monitoring. German Study Group on Mycophenolate
© 2007 Adis Data Information BV. All rights reserved.
55
Mofetil Therapy in Pediatric Renal Transplant Recipients.
Ther Drug Monit 2000; 22 (1): 20-6
111. Kuypers DR, Claes K, Evenepoel P, et al. Long-term changes in
mycophenolic acid exposure in combination with tacrolimus
and corticosteroids are dose dependent and not reflected by
trough plasma concentration: a prospective study in 100 de
novo renal allograft recipients. J Clin Pharmacol 2003; 43 (8):
866-80
112. Buchler M, Lebranchu Y, Beneton M, et al. Higher exposure to
mycophenolic acid with sirolimus than with cyclosporine co-
treatment. Clin Pharmacol Ther 2005; 78 (1): 34-42
113. van Gelder T, Klupp J, Barten MJ, et al. Comparison of the
effects of tacrolimus and cyclosporine on the pharmacokinet-
ics of mycophenolic acid. Ther Drug Monit 2001; 23 (2):
119-28
114. Pou L, Brunet M, Cantarell C, et al. Mycophenolic acid plasma
concentrations: influence of comedication. Ther Drug Monit
2001; 23 (1): 35-8
115. Filler G, Zimmering M, Mai I. Pharmacokinetics of mycophe-
nolate mofetil are influenced by concomitant immunosuppres-
sion. Pediatr Nephrol 2000; 14 (2): 100-4
116. Picard N, Premaud A, Rousseau A, et al. A comparison of the
effect of cyclosporin and sirolimus on the pharmokinetics of
mycophenolate in renal transplant patients. Br J Clin
Pharmacol 2006 Oct; 62 (4): 477-84
117. Deters M, Kirchner G, Koal T, et al. Influence of cyclosporine
on the serum concentration and biliary excretion of mycophe-
nolic acid and 7-O-mycophenolic acid glucuronide. Ther Drug
Monit 2005; 27 (2): 132-8
118. El Haggan W, Ficheux M, Debruyne D, et al. Pharmacokinetics
of mycophenolic acid in kidney transplant patients receiving
sirolimus versus cyclosporine. Transplant Proc 2005; 37 (2):
864-6
119. Gregoor PJ, de Sevaux RG, Hene RJ, et al. Effect of
cyclosporine on mycophenolic acid trough levels in kidney
transplant recipients. Transplantation 1999; 68 (10): 1603-6
120. Hohage H, Zeh M, Heck M, et al. Differential effects of
cyclosporine and tacrolimus on mycophenolate
pharmacokinetics in patients with impaired kidney function.
Transplant Proc 2005; 37 (4): 1748-50
121. Hubner GI, Eismann R, Sziegoleit W. Drug interaction between
mycophenolate mofetil and tacrolimus detectable within thera-
peutic mycophenolic acid monitoring in renal transplant pa-
tients. Ther Drug Monit 1999; 21 (5): 536-9
122. Kaplan B, Meier-Kriesche HU, Minnick P, et al. Randomized
calcineurin inhibitor cross over study to measure the
pharmacokinetics of co-administered enteric-coated mycophe-
nolate sodium. Clin Transplant 2005; 19 (4): 551-8
123. Shipkova M, Armstrong VW, Kuypers D, et al. Effect of
cyclosporine withdrawal on mycophenolic acid
pharmacokinetics in kidney transplant recipients with deterio-
rating renal function: preliminary report. Ther Drug Monit
2001; 23 (6): 717-21
124. Smak Gregoor PJ, van Gelder T, Hesse CJ, et al. Mycophenolic
acid plasma concentrations in kidney allograft recipients with
or without cyclosporin: a cross-sectional study. Nephrol Dial
Transplant 1999; 14 (3): 706-8
125. Kiberd BA, Puthenparumpil JJ, Fraser A, et al. Impact of
mycophenolate mofetil loading on drug exposure in the early
posttransplant period. Transplant Proc 2005; 37 (5): 2320-3
126. Kuriata-Kordek M, Boratynska M, Falkiewicz K, et al. The
influence of calcineurin inhibitors on mycophenolic acid
pharmacokinetics. Transplant Proc 2003; 35 (6): 2369-71
127. Zucker K, Rosen A, Tsaroucha A, et al. Unexpected augmenta-
tion of mycophenolic acid pharmacokinetics in renal transplant
patients receiving tacrolimus and mycophenolate mofetil in
combination therapy, and analogous in vitro findings. Transpl
Immunol 1997; 5 (3): 225-32
Clin Pharmacokinet 2007; 46 (1)
56
128. Cremers S, Schoemaker R, Scholten E, et al. Characterizing the
role of enterohepatic recycling in the interactions between
mycophenolate mofetil and calcineurin inhibitors in renal
transplant patients by pharmacokinetic modelling. Br J Clin
Pharmacol 2005; 60 (3): 249-56
129. Cattaneo D, Perico N, Gaspari F, et al. Glucocorticoids interfere
with mycophenolate mofetil bioavailability in kidney trans-
plantation. Kidney Int 2002; 62 (3): 1060-7
130. Mudge DW, Atcheson B, Taylor PJ, et al. The effect of oral iron
administration on mycophenolate mofetil absorption in renal
transplant recipients: a randomized, controlled trial. Trans-
plantation 2004; 77 (2): 206-9
131. Lorenz M, Wolzt M, Weigel G, et al. Ferrous sulfate does not
affect mycophenolic acid pharmacokinetics in kidney trans-
plant patients. Am J Kidney Dis 2004; 43 (6): 1098-103
132. Mai I, Stormer E, Bauer S, et al. Impact of St John’s wort
treatment on the pharmacokinetics of tacrolimus and
mycophenolic acid in renal transplant patients. Nephrol Dial
Transplant 2003; 18 (4): 819-22
133. Lu XY, Huang HF, Sheng-Tu JZ, et al. Pharmacokinetics of
mycophenolic acid in Chinese kidney transplant patients. J
Zhejiang Univ Sci B 2005; 6 (9): 885-91
134. Kuypers DR, Verleden G, Naesens M, et al. Drug interaction
between mycophenolate mofetil and rifampin: possible induc-
tion of uridine diphosphate-glucuronosyltransferase. Clin
Pharmacol Ther 2005; 78 (1): 81-8
135. Pieper AK, Buhle F, Bauer S, et al. The effect of sevelamer on
the pharmacokinetics of cyclosporin A and mycophenolate
mofetil after renal transplantation. Nephrol Dial Transplant
2004; 19 (10): 2630-3
136. Zucker K, Tsaroucha A, Olson L, et al. Evidence that tacrolimus
augments the bioavailability of mycophenolate mofetil
through the inhibition of mycophenolic acid glucuronidation.
Ther Drug Monit 1999; 21 (1): 35-43
137. Hesselink DA, van Hest RM, Mathot RA, et al. Cyclosporine
interacts with mycophenolic Acid by inhibiting the multidrug
resistance-associated protein 2. Am J Transplant 2005; 5 (5):
987-94
138. Vidal E, Cantarell C, Capdevila L, et al. Mycophenolate mofetil
pharmacokinetics in transplant patients receiving cyclosporine
or tacrolimus in combination therapy. Pharmacol Toxicol
2000; 87 (4): 182-4
139. Meiser BM, Groetzner J, Kaczmarek I, et al. Tacrolimus or
cyclosporine: which is the better partner for mycophenolate
mofetil in heart transplant recipients? Transplantation 2004; 78
(4): 591-8
140. Smak Gregoor PJ, de Sevaux RG, Hene RJ, et al. Effect of
cyclosporine on mycophenolic acid trough levels in kidney
transplant recipients. Transplantation 1999; 68 (10): 1603-6
141. Kato R, Ooi K, Ikura-Mori M, et al. Impairment of mycopheno-
late mofetil absorption by calcium polycarbophil. J Clin
Pharmacol 2002; 42 (11): 1275-80
142. Morii M, Ueno K, Ogawa A, et al. Impairment of mycopheno-
late mofetil absorption by iron ion. Clin Pharmacol Ther 2000;
68 (6): 613-6
143. Gimenez F, Foeillet E, Bourdon O, et al. Evaluation of
pharmacokinetic interactions after oral administration of
mycophenolate mofetil and valaciclovir or aciclovir to healthy
subjects. Clin Pharmacokinet 2004; 43 (10): 685-92
144. Wolfe EJ, Mathur V, Tomlanovich S, et al. Pharmacokinetics of
mycophenolate mofetil and intravenous ganciclovir alone and
in combination in renal transplant recipients. Pharmacotherapy
1997; 17 (3): 591-8
145. Schmidt LE, Rasmussen A, Norrelykke MR, et al. The effect of
selective bowel decontamination on the pharmacokinetics of
mycophenolate mofetil in liver transplant recipients. Liver
Transpl 2001; 7 (8): 739-42
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
146. Girard H, Court MH, Bernard O, et al. Identification of common
polymorphisms in the promoter of the UGT1A9 gene: evi-
dence that UGT1A9 protein and activity levels are strongly
genetically controlled in the liver. Pharmacogenetics 2004; 14
(8): 501-15
147. Cattaneo D, Perico N, Remuzzi G. From pharmacokinetics to
pharmacogenomics: a new approach to tailor immunosuppres-
sive therapy. Am J Transplant 2004; 4 (3): 299-310
148. Del Tacca M. Prospects for personalized immunosuppression:
pharmacologic tools: a review. Transplant Proc 2004; 36 (3):
687-9
149. Fisher MB, Paine MF, Strelevitz TJ, et al. The role of hepatic
and extrahepatic UDP-glucuronosyltransferases in human
drug metabolism. Drug Metab Rev 2001; 33 (3-4): 273-97
150. Villeneuve L, Girard H, Fortier LC, et al. Novel functional
polymorphisms in the UGT1A7 and UGT1A9 glucuronidating
enzymes in Caucasian and African-American subjects and
their impact on the metabolism of 7-ethyl-10-hydroxy-
camptothecin and flavopiridol anticancer drugs. J Pharmacol
Exp Ther 2003; 307 (1): 117-28
151. Jinno H, Saeki M, Saito Y, et al. Functional characterization of
human UDP-glucuronosyltransferase 1A9 variant, D256N,
found in Japanese cancer patients. J Pharmacol Exp Ther 2003;
306 (2): 688-93
152. Beal JL, Jones CE, Taylor PJ, et al. Evaluation of an immunoas-
say (EMIT) for mycophenolic acid in plasma from renal trans-
plant recipients compared with a high-performance liquid
chromatography assay. Ther Drug Monit 1998; 20 (6): 685-90
153. Premaud A, Debord J, Rousseau A, et al. A double absorption-
phase model adequately describes mycophenolic acid plasma
profiles in de novo renal transplant recipients given oral
mycophenolate mofetil. Clin Pharmacokinet 2005; 44 (8):
837-47
154. Payen S, Zhang D, Maisin A, et al. Population pharmacokinetics
of mycophenolic acid in kidney transplant pediatric and ado-
lescent patients. Ther Drug Monit 2005; 27 (3): 378-88
155. Tredger JM, Brown NW, Adams J, et al. Monitoring mycophe-
nolate in liver transplant recipients: toward a therapeutic range.
Liver Transpl 2004; 10 (4): 492-502
156. Kuypers DR, Claes K, Evenepoel P, et al. Clinical efficacy and
toxicity profile of tacrolimus and mycophenolic acid in rela-
tion to combined long-term pharmacokinetics in de novo renal
allograft recipients. Clin Pharmacol Ther 2004; 75 (5): 434-47
157. Pillans PI, Rigby RJ, Kubler P, et al. A retrospective analysis of
mycophenolic acid and cyclosporin concentrations with acute
rejection in renal transplant recipients. Clin Biochem 2001; 34
(1): 77-81
158. Okamoto M, Wakabayashi Y, Higuchi A, et al. Therapeutic
drug monitoring of mycophenolic acid in renal transplant
recipients. Transplant Proc 2005; 37 (2): 859-60
159. Lu YP, Lin B, Liang MZ, et al. Correlation of mycophenolic
acid pharmacokinetic parameters with side effects in Chinese
kidney transplant recipients treated with mycophenolate mofe-
til. Transplant Proc 2004; 36 (7): 2079-81
160. Kuriata-Kordek M, Boratynska M, Klinger M, et al. The effica-
cy of mycophenolate mofetil treatment in the prevention of
acute renal rejection is related to plasma level of mycophenolic
acid. Transplant Proc 2002; 34 (7): 2985-7
161. van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A ran-
domized double-blind, multicenter plasma concentration con-
trolled study of the safety and efficacy of oral mycophenolate
mofetil for the prevention of acute rejection after kidney
transplantation. Transplantation 1999; 68 (2): 261-6
162. Takahashi K, Ochiai T, Uchida K, et al. Pilot study of mycophe-
nolate mofetil (RS-61443) in the prevention of acute rejection
following renal transplantation in Japanese patients. RS-61443
Investigation Committee – Japan. Transplant Proc 1995; 27
(1): 1421-4
Clin Pharmacokinet 2007; 46 (1)
PK and PD of Mycophenolate in Solid Organ Transplantation
163. Smak Gregoor PJ, van Gelder T, van Besouw NM, et al.
Mycophenolic acid trough levels after kidney transplantation
in a cyclosporine-free protocol. Transpl Int 2000; 13 Suppl. 1:
S333-5
164. Krumme B, Wollenberg K, Kirste G, et al. Drug monitoring of
mycophenolic acid in the early period after renal transplanta-
tion. Transplant Proc 1998; 30 (5): 1773-4
165. Hesse CJ, Vantrimpont P, van Riemsdijk-van Overbeeke IC, et
al. The value of routine monitoring of mycophenolic acid
plasma levels after clinical heart transplantation. Transplant
Proc 2001; 33 (3): 2163-4
166. Meiser BM, Pfeiffer M, Schmidt D, et al. Combination therapy
with tacrolimus and mycophenolate mofetil following cardiac
transplantation: importance of mycophenolic acid therapeutic
drug monitoring. J Heart Lung Transplant 1999; 18 (2): 143-9
167. Yamani MH, Starling RC, Goormastic M, et al. The impact of
routine mycophenolate mofetil drug monitoring on the treat-
ment of cardiac allograft rejection. Transplantation 2000; 69
(11): 2326-30
168. Gajarski RJ, Crowley DC, Zamberlan MC, et al. Lack of corre-
lation between MMF dose and MPA level in pediatric and
young adult cardiac transplant patients: does the MPA level
matter? Am J Transplant 2004; 4 (9): 1495-500
169. Weber LT, Schutz E, Lamersdorf T, et al. Therapeutic drug
monitoring of total and free mycophenolic acid (MPA) and
limited sampling strategy for determination of MPA-AUC in
paediatric renal transplant recipients. The German Study
Group on Mycophenolate Mofetil (MMF) Therapy. Nephrol
Dial Transplant 1999; 14 Suppl. 4: 34-5
170. Cox VC, Ensom MH. Mycophenolate mofetil for solid organ
transplantation: does the evidence support the need for clinical
pharmacokinetic monitoring? Ther Drug Monit 2003; 25 (2):
137-57
171. Smak Gregoor PJ, Hesse CJ, van Gelder T, et al. Relation of
mycophenolic acid trough levels and adverse events in kidney
allograft recipients. Transplant Proc 1998; 30 (4): 1192-3
172. Cattaneo D, Gaspari F, Ferrari S, et al. Pharmacokinetics help
optimizing mycophenolate mofetil dosing in kidney transplant
patients. Clin Transplant 2001; 15 (6): 402-9
173. Mourad M, Malaise J, Chaib Eddour D, et al. Pharmacokinetic
basis for the efficient and safe use of low-dose mycophenolate
mofetil in combination with tacrolimus in kidney transplanta-
tion. Clin Chem 2001; 47 (7): 1241-8
174. Hubner GI, Eismann R, Sziegoleit W. Relationship between
mycophenolate mofetil side effects and mycophenolic acid
plasma trough levels in renal transplant patients. Arzneimittel
Forschung 2000; 50 (10): 936-40
175. Kaplan B, Gruber SA, Nallamathou R, et al. Decreased protein
binding of mycophenolic acid associated with leukopenia in a
pancreas transplant recipient with renal failure. Transplanta-
tion 1998; 65 (8): 1127-9
176. Behrend M. Adverse gastrointestinal effects of mycophenolate
mofetil: aetiology, incidence and management. Drug Saf 2001;
24 (9): 645-63
177. Shaw LM, Sollinger HW, Halloran P, et al. Mycophenolate
mofetil: a report of the consensus panel. Ther Drug Monit
1995; 17 (6): 690-9
178. Shaw LM, Nicholls A, Hale M, et al. Therapeutic monitoring of
mycophenolic acid: a consensus panel report. Clin Biochem
1998; 31 (5): 317-22
179. Shaw LM, Korecka M, Venkataramanan R, et al. Mycophenolic
acid pharmacodynamics and pharmacokinetics provide a basis
for rational monitoring strategies. Am J Transplant 2003; 3 (5):
534-42
180. Nicholls AJ. Opportunities for therapeutic monitoring of
mycophenolate mofetil dose in renal transplantation suggested
by the pharmacokinetic/pharmacodynamic relationship for
© 2007 Adis Data Information BV. All rights reserved.
57
mycophenolic acid and suppression of rejection. Clin Biochem
1998; 31 (5): 329-33
181. Willis C, Taylor PJ, Salm P, et al. Quantification of free
mycophenolic acid by high-performance liquid chromatogra-
phy-atmospheric pressure chemical ionisation tandem mass
spectrometry. J Chromatogr B Biomed Sci Appl 2000; 748 (1):
151-6
182. Jones CE, Taylor PJ, Johnson AG. High-performance liquid
chromatography determination of mycophenolic acid and its
glucuronide metabolite in human plasma. J Chromatogr B
Biomed Sci Appl 1998; 708 (1-2): 229-34
183. Teshima D, Otsubo K, Kitagawa N, et al. High-performance
liquid chromatographic method for mycophenolic acid and its
glucuronide in serum and urine. J Clin Pharm Ther 2003; 28
(1): 17-22
184. Streit F, Shipkova M, Armstrong VW, et al. Validation of a
rapid and sensitive liquid chromatography-tandem mass spec-
trometry method for free and total mycophenolic acid. Clin
Chem 2004; 50 (1): 152-9
185. Atcheson B, Taylor PJ, Mudge DW, et al. Quantification of free
mycophenolic acid and its glucuronide metabolite in human
plasma by liquid-chromatography using mass spectrometric
and ultraviolet absorbance detection. J Chromatogr B Analyt
Technol Biomed Life Sci 2004; 799 (1): 157-63
186. Premaud A, Rousseau A, Le Meur Y, et al. Comparison of liquid
chromatography-tandem mass spectrometry with a commer-
cial enzyme-multiplied immunoassay for the determination of
plasma MPA in renal transplant recipients and consequences
for therapeutic drug monitoring. Ther Drug Monit 2004; 26
(6): 609-19
187. Schutz E, Shipkova M, Armstrong VW, et al. Therapeutic drug
monitoring of mycophenolic acid: comparison of HPLC and
immunoassay reveals new MPA metabolites. Transplant Proc
1998; 30 (4): 1185-7
188. Shipkova M, Schutz E, Armstrong VW, et al. Overestimation of
mycophenolic acid by EMIT correlates with MPA metabolite.
Transplant Proc 1999; 31 (1-2): 1135-7
189. Filler G, Mai I. Limited sampling strategy for mycophenolic
acid area under the curve. Ther Drug Monit 2000; 22 (2):
169-73
190. Willis C, Taylor PJ, Salm P, et al. Evaluation of limited sam-
pling strategies for estimation of 12-hour mycophenolic acid
area under the plasma concentration-time curve in adult renal
transplant patients. Ther Drug Monit 2000; 22 (5): 549-54
191. Yeung S, Tong KL, Tsang WK, et al. Determination of
mycophenolate area under the curve by limited sampling strat-
egy. Transplant Proc 2001; 33 (1-2): 1052-3
192. Pawinski T, Hale M, Korecka M, et al. Limited sampling
strategy for the estimation of mycophenolic acid area under the
curve in adult renal transplant patients treated with concomi-
tant tacrolimus. Clin Chem 2002; 48 (9): 1497-504
193. Schutz E, Armstrong VW, Shipkova M, et al. Limited sampling
strategy for the determination of mycophenolic acid area under
the curve in pediatric kidney recipients. German Study Group
on MMF Therapy in Pediatric Renal Transplant Recipients.
Transplant Proc 1998; 30 (4): 1182-4
194. Premaud A, Le Meur Y, Debord J, et al. Maximum a posteriori
bayesian estimation of mycophenolic acid pharmacokinetics in
renal transplant recipients at different postgrafting periods.
Ther Drug Monit 2005; 27 (3): 354-61
195. Budde K, Glander P, Bauer S, et al. Pharmacodynamic monitor-
ing of mycophenolate mofetil. Clin Chem Lab Med 2000; 38
(11): 1213-6
196. van Gelder T. Mycophenolate mofetil: how to further improve
using an already successful drug? Am J Transplant 2005; 5 (2):
199-200
197. Weigel G, Griesmacher A, Karimi A, et al. Effect of mycophe-
nolate mofetil therapy on lymphocyte activation in heart trans-
Clin Pharmacokinet 2007; 46 (1)
58
plant recipients. J Heart Lung Transplant 2002; 21 (10):
1074-9
198. Sanquer S, Breil M, Baron C, et al. Induction of inosine
monophosphate dehydrogenase activity after long-term treat-
ment with mycophenolate mofetil. Clin Pharmacol Ther 1999;
65 (6): 640-8
199. Goldsmith D, Carrey EA, Edbury S, et al. Mycophenolate
mofetil, an inhibitor of inosine monophosphate
dehydrogenase, causes a paradoxical elevation of GTP in
erythrocytes of renal transplant patients. Clin Sci (Lond) 2004;
107 (1): 63-8
200. Glander P, Hambach P, Braun KP, et al. Effect of mycopheno-
late mofetil on IMP dehydrogenase after the first dose and after
long-term treatment in renal transplant recipients. Int J Clin
Pharmacol Ther 2003; 41 (10): 470-6
201. Jagodzinski P, Lizakowski S, Smolenski RT, et al. Mycopheno-
late mofetil treatment following renal transplantation de-
creases GTP concentrations in mononuclear leucocytes. Clin
Sci (Lond) 2004; 107 (1): 69-74
202. Glander P, Braun KP, Hambach P, et al. Non-radioactive deter-
mination of inosine 5′-monophosphate dehydro-genase
© 2007 Adis Data Information BV. All rights reserved.
Staatz & Tett
(IMPDH) in peripheral mononuclear cells. Clin Biochem
2001; 34 (7): 543-9
203. Glander P, Hambach P, Braun KP, et al. Pre-transplant inosine
monophosphate dehydrogenase activity is associated with
clinical outcome after renal transplantation. Am J Transplant
2004; 4 (12): 2045-51
204. Vannozzi F, Filipponi F, Di Paolo A, et al. An exploratory study
on pharmacogenetics of inosine-monophosphate
dehydrogenase II in peripheral mononuclear cells from liver-
transplant recipients. Transplant Proc 2004; 36 (9): 2787-90
205. Kuypers DR. Immunosuppressive drug monitoring: what to use
in clinical practice today to improve renal graft outcome.
Transpl Int 2005; 18 (2): 140-50
Correspondence and offprints: Dr Christine E. Staatz, School
of Pharmacy, University of Queensland, Brisbane, QLD
4072, Australia.
E-mail: chris@pharmacy.uq.edu.au
Clin Pharmacokinet 2007; 46 (1)