Nephrol Dial Transplant (2020) 35: 1060–1070

doi: 10.1093/ndt/gfaa111

Effect of the proton-pump Inhibitor pantoprazole on

MycoPhenolic ACid exposure in kidney and liver transplant
ORIGINAL ARTICLE

recipienTs (IMPACT study): a randomized trial

Andrew Sunderland1, Graeme Russ2, Benedetta Sallustio3,4, Matthew Cervelli5, David Joyce6,7,8,

Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023

Esther Ooi6,8, Gary Jeffrey8,9, Neil Boudville1,8, Aron Chakera1, Gursharan Dogra1, Doris Chan1,
Germaine Wong10,11,12 and Wai H. Lim1,8
1
Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, Australia, 2Department of Nephrology & Transplantation Services,
Royal Adelaide Hospital, and University of Adelaide, Adelaide, Australia, 3Discipline of Pharmacology, Adelaide Medical School, The University
of Adelaide, Adelaide, Australia, 4Department of Clinical Pharmacology, The Queen Elizabeth Hospital, Adelaide, Australia, 5Department of
Pharmacy, Royal Adelaide Hospital, Adelaide, Australia, 6School of Biomedical Sciences, University of Western Australia, Perth, Australia,
7
Biochemistry and Toxicology, PathWest, Perth, Australia, 8Faculty of Health and Medical Sciences, Medical School, University of Western
Australia, Perth, Australia, 9Department of Hepatology Unit, Sir Charles Gairdner Hospital, Perth, Australia, 10Sydney School of Public Health,
University of Sydney, Sydney, Australia, 11Centre for Transplant and Renal Research, Westmead Hospital, Sydney, Australia and 12Centre for
Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia

Correspondence to: Wai H. Lim; E-mail: wai.lim@health.wa.gov.au

GRAPHICAL ABSTRACT

In kidney and liver transplant patients, co-administration of pantoprazole reduces

RCT bioavailability of mycophenolic acid from mycophenolate mofetil (MMF), but
increases bioavailability from enteric-coated mycophenolic acid salts (EC-MPS)

Trial characteristics Trial design Primary outcome

2 centres (Australia) Placebo Placebo Placebo
n = 40 participants n=9 n = 10 53.9
MMF
Age > 18 years PPI PPI MPA–AUC PPI
Kidney/liver transplant > 6 months
(n = 19) mg*hr/L 43.8
n = 10 n=9
P = 0.004
Current medication:
Treatment Washout Treatment Bioavailabilty of
MMF ≥ 1 g daily or
7 days 7 days 7 days
EC-MPS ≥ 1080 mg daily mycophenolic acid
Intervention: Placebo Placebo Placebo
Pantoprazole 40 mg daily n = 11 n = 10 36.1
Primary endpoint: EC-MPS MPA–AUC PPI
PPI PPI
12 hr bioavailability of (n = 21) n = 10 n = 11 mg*hr/L 45.9
mycophenolic acid (MPA–AUC) P = 0.023

Sunderland A, et al. NDT (2020)

@NDTSocial

ABSTRACT concentrations and adverse allograft outcome. Proton-pump

Background. Mycophenolic acid (MPA) is widely utilized as an inhibitors (PPIs) may have variable effects on the absorption of
immunosuppressant in kidney and liver transplantation, with different MPA formulations leading to differences in MPA
reports suggesting an independent relationship between MPA exposure.
C The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
V 1060
Methods. A multicentre, randomized, prospective, double-
blind placebo-controlled cross-over study was conducted to de-
termine the effect of the PPI pantoprazole on the MPA and its
metabolite MPA-glucuronide (MPA-G) area under the curve
(AUC) >12 h (MPA-AUC12 h) in recipients maintained on
mycophenolate mofetil (MMF) or enteric-coated mycopheno-
late sodium (EC-MPS). We planned a priori to examine sepa-
rately recipients maintained on MMF and EC-MPS for each
pharmacokinetic parameter. The trial (and protocol) was regis-
tered with the Australian New Zealand Clinical Trials Registry
on 24 March 2011, with the registration number of
ACTRN12611000316909 (‘IMPACT’ study).
Results. Of the 45 recipients screened, 40 (19 MMF and 21 EC-
MPS) were randomized. The mean (standard deviation) recipient
age was 58 (11) years with a median (interquartile range) time
post-transplant of 43 (20–132) months. For recipients on MMF,
there was a significant reduction in the MPA-AUC12 h [geometric
mean (95% confidence interval) placebo: 53.9 (44.0–65.9) mg*h/
L versus pantoprazole: 43.8 (35.6–53.4) mg*h/L; P ¼ 0.004] when
pantoprazole was co-administered compared with placebo. In
contrast, co-administration with pantoprazole significantly in-
creased MPA-AUC12 h [placebo: 36.1 (26.5–49.2) mg*h/L versus
pantoprazole: 45.9 (35.5–59.3) mg*h/L; P ¼ 0.023] in those re-
ceiving EC-MPS. Pantoprazole had no effect on the pharmacoki-
netic profiles of MPA-G for either group.
Conclusions. The co-administration of pantoprazole substantially
reduced the bioavailability of MPA in patients maintained on
MMF and had the opposite effect in patients maintained on EC-
MPS, and therefore, clinicians should be cognizant of this drug in-
teraction when prescribing the different MPA formulations.
Keywords: drug interaction, enteric-coated mycophenolate
sodium, kidney transplant, mycophenolate, mycophenolic
acid, pharmacokinetic, proton-pump inhibitor
INTRODUCTION
Mycophenolic acid (MPA) is available as the ester pro-drug
R
mycophenolate mofetil (MMF, CellceptV) or as the enteric-
coated salt form mycophenolate sodium (EC-MPS, MyforticV).
R
Immunosuppressive regimens containing MPA are widely uti-
lized in kidney and liver transplantation to reduce rejection
rates and improve allograft survival [1]. There has been consid-
erable interest in individualizing MMF or EC-MPS dosing
according to therapeutic drug monitoring (TDM) to reduce ad-
verse events associated with these drugs while improving clini-
cal outcomes. The APOMYGRE and OPTICEPT trials suggest
that adjustment of MMF dosing according to therapeutic MPA
monitoring could reduce the risk of treatment failure, including
rejection, but the impact of MPA monitoring on longer term al-
lograft outcome remains unclear [2–5]. Consequently, MPA
TDM has not been widely adopted into clinical practice among
transplanting centres.
Peptic ulcer disease is a common complication following kid-
ney and liver transplantation and therefore prophylactic proton-
pump inhibitors (PPIs) are often prescribed in these patients to
reduce the risk of symptomatic peptic ulcer or gastro-
Effect of pantoprazole on MPA exposure
KEY LEARNING POINTS
What is already known about this subject?
• Proton-pump inhibitors (PPIs) could reduce the sys-
temic exposure of mycophenolic acid (MPA) for
patients maintained on mycophenolate mofetil (MMF)
formulation but not in those maintained on enteric-
coated salt form mycophenolate sodium (EC-MPS),
but this drug–drug interaction has not been confirmed
in adequately powered randomized controlled trial in
solid organ transplant recipients.
What this study adds?
• This randomized placebo-controlled cross-over study
Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023
showed that the co-administration of pantoprazole
substantially reduced the bioavailability of MPA in
kidney and liver transplant recipients maintained on
MMF and had the opposite effect in patients main-
tained on EC-MPS.
What impact this may have on practice or policy?
• Clinicians should be cognizant of this drug interaction
when prescribing PPIs with MMF or EC-MPS, but the
longer term clinical effect of this drug–drug interac-
tion in kidney and liver transplant recipients remains
unknown.
oesophageal reflux disease [6]. It has been shown that by increas-
ing gastric pH and thus reducing the solubility of MMF in the
gut, PPIs could reduce the systemic exposure of MPA for patients
on MMF but not EC-MPS [7–9]. This effect may lead to inade-
quate immunosuppression with an increased risk of rejection.
This important effect of PPIs on MPA pharmacokinetics follow-
ing MMF or EC-MPS administration remains poorly recognized
and should be taken into consideration with regard to appropri-
ate dosing of MMF and EC-MPS in kidney and liver transplant
recipients. In a single-dose cross-over study of 12 healthy volun-
teers, the concomitant administration of pantoprazole signifi-
cantly reduced MPA exposure following MMF treatment (dose
1 g daily), which was not evident following EC-MPS (720 mg
daily) treatment [10]. In stable kidney and liver transplant recipi-
ents, we aimed to compare the effects of a PPI versus placebo on
MPA exposure in those maintained on MMF or EC-MPS.
MATERIALS AND METHODS
This was a multicentre, randomized, prospective, double-
blinded, placebo-controlled, cross-over study to assess the effect
of gastric acid suppression (PPI pantoprazole) on the pharma-
cokinetics of MPA in kidney or liver transplant recipients main-
tained on MMF or EC-MPS. This trial was conducted in two
transplanting centres in Australia (Sir Charles Gairdner
Hospital, Perth; Royal Adelaide Hospital (RAH), Adelaide].
Local institutional ethics committees at each site approved the
study and written consents were obtained from participants
prior to randomization. The trial (and protocol) was registered
1061
with the Australian New Zealand Clinical Trials Registry on 24
March 2011, with the registration number of
ACTRN12611000316909 (‘IMPACT’ study).
Study population
The target population comprised stable adult (>18 years)
kidney and liver transplant recipients who were 6 months
post-transplant. Recipients were maintained on MMF (1 g
daily) or EC-MPS (1080 mg daily) in two equally divided
doses. If recipients were maintained on unequal twice daily dos-
ing, then they agreed to alter to two equally divided dose for
2 weeks prior to trial enrolment. Other inclusion criteria for the
trial were recipients who were willing to change to pantoprazole
(from other PPI or H2-blocker) or willing to start pantoprazole
if not already on this drug, maintained on a stable dose of calci-
neurin inhibitor (CNI; cyclosporine or tacrolimus) and were ca-
pable of providing written informed consent. Exclusion criteria
included recipients maintained on non-CNI agents except cor-
ticosteroids; recent change (<2 weeks) in the total dose of corti-
costeroids, CNI, MMF or EC-MPS; recent acute rejection
(defined as biopsy-proven acute rejection episode requiring in-
tervention within 1 month prior to randomization);
Modification of Diet in Renal Disease Study-derived estimated
glomerular filtration rate (eGFR) of <20 mL/min/1.73 m2; and
significant peptic ulcer disease or ulcerative esophagitis (based
on medical history) where withdrawal of acid suppression ther-
apy is not clinically appropriate, and concurrent use of magne-
sium- or aluminium-based antacid or cholestyramine.
Study design
For recipients who were maintained on PPI and/or H2-
blocker, this was ceased 14 days prior to randomization.
Recipients were given two packets of study medications clearly
labelled Pack A and B. Recipients were advised to commence
study medication from Pack A (containing either placebo or
pantoprazole, one tablet daily for 7 days; Days 1–7) and then
admitted on the morning of the first pharmacokinetic study
(Day 8). The previous dose of MMF or EC-MPS was taken 12 h
prior to the first blood sample (Time 0). Following the initial ve-
nous blood sampling, the recipients took the morning dose of
MMF or EC-MPS, along with the CNI and other usual medica-
tions as prescribed. Venous blood samplings occurred at time
point 0, and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10 and 12 h post
MMF or EC-MPS dose. The blood samples were centrifuged
and plasma separated and stored at 70 C until analysis.
Following the completion of the first visit, the recipients were
advised to continue on the usual medications for the next 7 days
without any study medications (washout period; Days 8–14).
On Day 15, the recipients were advised to commence study
medication from Pack B (containing either placebo or panto-
prazole, one tablet daily for 7 days; Days 15–21), and then re-
admitted on Day 22 for the second pharmacokinetic study. A
telephone call reminder was scheduled at Day 14 and a compli-
ance check of study medication was undertaken at each phar-
macokinetic study visit.
Study drug
The study medications of pantoprazole (40 mg) and match-
ing placebo were prepared by Pharmaceutical Packaging
1062
Professionals (Victoria, Australia) on the advice of the clinical
pharmacologist from RAH. The pantoprazole (commercial
product) pills were de-blistered and placed into an empty gela-
tine capsule and then filled with lactose or other inert filler to
disguise their content. The placebo was made by encapsulating
lactose in an identical soft gelatine capsule. Both capsules were
indistinguishable visually or by smell from the matching pla-
cebo, and dissolved completely once ingested. The trial pharma-
cists at the RAH prepared two packs labelled Packs A and B,
with each pack containing seven tablets of pantoprazole or
matching placebo, with packs shipped to Perth. The package of
either study medication into Pack A or B was random, under-
taken by the trial pharmacist of RAH. The selection of the pack-
age of either study medication for each recipient was
Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023
undertaken by the trial pharmacy team of each site independent
of the study according to a pre-specified allocation sequence.
The study investigators, study coordinators and recipients were
blinded to the study medications. There were 56 study medica-
tion packs prepared, with each pack containing Packs A and B
(16 packs were unused/expired and discarded). These packs
were block randomized for the two sites and for liver and kid-
ney transplant recipients.
Clinical endpoints
The primary endpoint of this study was the pharmacokinetic
profile of MPA and MPA-glucuronide (MPA-G) when co-
administered with placebo or pantoprazole, expressed as
MPA-area under the curve (AUC) and MPA-G AUC >12 h
(MPA-AUC12 h and MPAG-AUC12 h, respectively), maximum
concentration (Cmax) and time to Cmax (Tmax). Dose-
normalized AUC12 h and Cmax for MPA and MPA-G were cal-
culated for a 2 g daily dose of MMF or 1440 mg daily dose of
EC-MPS. Secondary endpoints included any biopsy-proven
acute rejection, allograft failure and adverse events (as assessed
by site investigators) during and for 2 weeks following the com-
pletion of the study.
Measurements of MPA and MPA-G
Plasma was analysed for MPA and MPA-G using a validated
high-performance liquid chromatography-ultraviolet-based
method detection assay [11]. The area under the plasma MPA
and MPA-G concentration–time curves (i.e. AUC) to the last
quantifiable concentration (AUCt) were calculated using the
log-trapezoidal rule. All assays were performed in a laboratory
accredited by the National Association of Testing Authorities,
Australia (The Queen Elizabeth Hospital, Adelaide, Australia)
that subscribes to an external quality assurance programme for
MPA. The intra-assay precision and accuracy for MPA were es-
timated at calibrator concentrations at 0.5 and 20 mg/L and for
MPA-G at calibrator concentrations of 5 and 200 mg/L. Inter-
assay precision and accuracy of quality control samples were
determined for MPA at 2 and 15 mg/L and for MPA-G at 20
and 150 mg/L. Coefficients of variation were <5.0% and biases
were <14.0% for each concentration of each analyte.
Sample size calculation
The sample size calculation was derived from the randomized
cross-over study in healthy volunteers by Rupprecht et al. [10],
A. Sunderland et al.
 Total participants consented (n=45)
44 kidney transplant recipients + 1 liver transplant recipient

4 screen failures
and not randomized

Total participants randomized (n=41)

40 kidney transplant recipients + 1 liver transplant recipient

1 withdrew consent
(medication change)

MMF (n=19) EC–MPS (n=21)

18 kidney transplants 21 kidney transplants

Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023

1 liver transplant 0 liver transplants

Period 1 Placebo (n=9) PPI (n=10) Placebo (n=11) PPI (n=10) Period 1
7 days 12h AUC 7 days 12h AUC

Washout period
(7 days)

Period 2 Placebo (n=10) PPI (n=9) Placebo (n=10) PPI (n=11) Period 2
7 days 12h AUC 7 days 12h AUC

FIGURE 1: The CONSORT flow diagram and trial design of the ‘IMPACT’ trial. Of 40 recipients who were randomized and had completed
R
the trial, 19 were maintained on MMF and 21 were maintained on EC-MPS (MyforticV). Recipients were randomized to the study medication
(i.e. placebo or PPI 40 mg of pantoprazole daily) for 7 days, followed by a wash-out period of 7 days and then the alternative study medication
for 7 days. Two 12-h pharmacokinetic profiles were undertaken at the completion of each study medication.

where 12 healthy subjects were sufficient to detect a significant
difference between MPA AUC12 h following self-administration
of MMF with and without pantoprazole (MMF 40.0 6 7.8 versus
MMF þ pantoprazole 29.3 6 7.4 mg*h/L; P < 0.001). Given the
effect size (of 25% reduction of MPA-AUC12 h) and the poten-
tial greater variability observed in this study, a sample size of 15
recipients maintained on MMF would be sufficient to detect a
significant difference in MPA-AUC12 h of 25% with and with-
out pantoprazole. A similar number will be recruited for recipi-
ents maintained on EC-MPS. We planned to recruit 42 recipients
(similar proportion of recipients maintained on MMF and EC-
MPS), assuming a drop-out rate of up to 30%.
pantoprazole for each pharmacokinetic parameter within each
study group of MMF and EC-MPS. The proportions of recipi-
ents in each study group with MPA-AUC12 h with thresholds of
>30, >40, >50 and >60 mg*h/L were determined, given the
MPA-AUC12 h threshold of 30–60 mg*h/L has been shown to
be associated with lower risk of acute rejection [2, 5, 12–14].
Two sensitivity analyses were undertaken: (i) excluding one
liver transplant recipient (for the MMF group) and (ii) stratified
by entry eGFR thresholds of 60 and >60 mL/min/1.73 m2. All
analyses were undertaken using Stata version 15.1 (StataCorp
LP, College Station, TX, USA), with P < 0.05 considered statis-
tically significant.

Statistical analysis
Data were expressed as number (percentage), mean [stan-
dard deviation (SD)] and median [interquartile range (IQR)]
for categorical, normally distributed and non-normally distrib-
uted continuous variables, respectively, stratified by the study
groups. We planned a priori to examine separately recipients
maintained on MMF and EC-MPS, and between the subgroups
of CNI types (cyclosporin and tacrolimus) for each pharmaco-
kinetic parameter. For MPA and MPA-G (6dose-normalized)
AUC12 h, Cmax and Tmax, the geometric means and 95% confi-
dence intervals (CIs) were derived, with Wilcoxon signed-rank
test used to test the difference between placebo versus
RESULTS
Forty-five liver and kidney transplant recipients were consented
and 41 underwent randomization (four screen failures prior to
randomization) between December 2011 and August 2017.
One recipient withdrew consent after randomization, resulting
in 40 recipients completing the study (39 kidney and 1 liver
transplant recipients). We were unable to recruit additional
liver transplant recipients over the 5-year period and therefore
had continued to recruit kidney transplant recipients until the
target study sample size was reached. The CONSORT flow dia-
gram for this trial is shown in Figure 1.

Effect of pantoprazole on MPA exposure 1063

 Table 1. Baseline characteristics of study participants

Baseline characteristics of study cohort MMF (n ¼ 19) EC-MPS (n ¼ 21) Total (n ¼ 40)
Age, mean (SD) 61.1 (28.9) 55.8 (12.3) 58.3 (11.0)
Gender
Male 10 (52.6) 17 (81.0) 27 (67.5)
Female 9 (47.4) 4 (19.0) 13 (32.5)
Weight, mean (SD), kg 79.9 (17.2) 92.1 (20.0) 86.1 (19.5)
Post-transplant, median (IQR), months 92 (37–185) 23 (15.5–51.0) 43.0 (20.5–131.7)
Transplant type
Kidney 18 (94.7) 21 (100.0) 39 (97.5)
Liver 1 (5.3) 0 (0.0) 1 (2.5)
Allograft function at randomization
Creatinine, mean (SD), lmol/L 120.1 (42.4) 122.2 (45.3) 121.2 (43.4)
eGFR, mean (SD), mL/min/1.73 m2 56.7 (23.9) 61.7 (24.5) 59.3 (24.0)
Year of transplant

Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023

1980–89 1 (5.3) 0 (0.0) 1 (2.5)
1990–99 5 (26.3) 1 (4.8) 6 (15.0)
2000–09 8 (42.1) 4 (19.0) 12 (30.0)
2010þ 5 (26.3) 16 (76.2) 21 (52.5)
Hospital
Sir Charles Gairdner Hospital 10 (52.6) 17 (81.0) 27 (67.5)
RAH 9 (47.4) 4 (19.0) 13 (32.5)
Prior PPI 7 (36.8) 12 (57.1) 19 (47.5)
CNI type (total daily dose)
Cyclosporin 8 (42.1) 6 (28.6) 14 (35.0)
Dose, median (IQR), mg 150 (112–200) 200 (150–200) 171.4 (42.6)
Tacrolimus 11 (57.9) 15 (71.4) 26 (65.0)
Dose, median (IQR), mg 3 (2–4) 4 (2–7) 4.2 (3.3)
MPA (total daily dose)
MMF, median (IQR), mg 1500 (1000–2000) – –
EC-MPS, median (IQR), mg – 1440 (1080–1440) –
Prednisolone (total daily dose)
Dose, median (IQR), mg 5 (0–5) 5 (5–6) 5.7 (1.3)
Randomized drug
First drug placebo 9 (47.4) 11 (52.3) 20 (50.0)
First drug pantoprazole 10 (52.6) 10 (47.7) 20 (50.0)
Data are expressed as n (%), mean and SD or as median (IQR).

Of the 40 recipients, 19 (47.5%) and 21 (52.5%) were main-
tained on MMF and EC-MPS, respectively. Six (31.6%) recipi-
ents were maintained on 2 g daily of MMF, and 11 (52.4%)
recipients were maintained on 1440 mg daily of EC-MPS at time
of randomization. Recipients maintained on EC-MPS were
younger and were more likely to be recent transplant recipients
compared with those on MMF. Mean eGFR was 57 mL/min/
1.73 m2 for recipients maintained on MMF compared with
62 mL/min/1.73 m2 for recipients maintained on EC-MPS. Of
the 19 recipients who were prescribed PPI prior to enrolment,
prior clinical symptom of gastro-oesophageal reflux disease was
the main indication for treatment. However, the ascertainment
of the diagnosis or results of prior gastroscopy were not col-
lected. Of recipients maintained on MMF, 58% were prescribed
tacrolimus, whereas 71% of those on EC-MPS were prescribed
tacrolimus. The median doses of CNI, MMF, EC-MPS and pred-
nisolone for MMF and EC-MPS groups are shown in Table 1.
and Cmax and dose-normalized MPA-AUC12 h and Cmax were
significantly lower with pantoprazole compared with placebo.
There were no significant changes for Tmax or for all parameters
for MPA-G with pantoprazole or placebo in both groups. For
recipients maintained on EC-MPS, MPA-AUC12 h and dose-
normalized MPA-AUC12 h were significantly increased by
25% with pantoprazole compared with placebo. There were
no significant changes for Cmax, Tmax or for all parameters for
MPA-G. The concentration–time profiles for MPA of recipients
maintained on MMF or EC-MPS 6 pantoprazole/placebo are
shown in Figure 2A and B, respectively.
Table 3 shows the proportion of recipients maintained on
MMF or EC-MPS with MPA-AUC12 h of pre-specified thresh-
olds. Almost 90% of recipients maintained on MMF had MPA-
AUC12 h of >30 mg*h/L, reducing to 68% with pantoprazole.
For recipients maintained on EC-MPS, 76% had MPA-AUC12 h
of >30 mg*h/L, increasing to 81% with pantoprazole.

Pharmacokinetics of MPA and MPA-G Cyclosporin and tacrolimus: pharmacokinetics of MPA

Table 2 shows the geometric means and 95% CI of MPA and and MPA-G
MPA-G concentrations for recipients maintained on MMF and Table 4 shows the geometric means and 95% CI of MPA-
EC-MPS, co-administered with placebo compared with panto- AUC12 h and Cmax concentrations for recipients maintained on
prazole. For recipients maintained on MMF, MPA-AUC12 h MMF and EC-MPS 6 placebo/pantoprazole and stratified by

1064 A. Sunderland et al.

 Table 2. Pharmacokinetic parameters of MPA and MPA-G with concomitant placebo versus pantoprazole in kidney and liver transplant recipients
maintained on MMF or EC-MPS

Pharmacokinetic parameters (MMF and EC-MPS) Intervention Geometric means (95% CI) P-value
MMF: MPA
AUC12 h, mg*h/L Placebo 53.9 (44.0–65.9) 0.004
Pantoprazole 43.6 (35.6–53.4)
Dose-normalized AUC12 h, mg*h/La Placebo 76.0 (59.1–97.8) 0.005
Pantoprazole 61.6 (47.0–80.7)
Cmax, mg/L Placebo 16.1 (12.6–20.6) 0.002
Pantoprazole 10.7 (8.5–13.6)
Dose-normalized Cmax, mg/La Placebo 22.8 (18.3–28.3) 0.002
Pantoprazole 15.2 (11.6–19.8)
Tmax, h Placebo 1.0 (0.5–2.7) 0.422
Pantoprazole 1.2 (0.8–1.6)
MMF: MPA-G

Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023

AUC12 h, mg*h/L Placebo 845.2 (678.2–1053.2) 0.856
Pantoprazole 825.8 (658.4–1035.8)
Dose-normalized AUC12 h, mg*h/La Placebo 1193.9 (955.7–1491.4) 0.747
Pantoprazole 1166.5 (920.2–1479.9)
Cmax, mg/L Placebo 99.5 (83.1–119.2) 0.573
Pantoprazole 94.4 (77.8–114.6)
Dose-normalized Cmax, mg/La Placebo 140.6 (119.0–166.1) 0.629
Pantoprazole 133.4 (108.7–163.7)
Tmax, h Placebo 2.2 (1.4–3.3) 0.639
Pantoprazole 2.3 (1.6–3.3)
EC-MPS: MPA
AUC12 h, mg*h/L Placebo 36.1 (26.5–49.2) 0.016
Pantoprazole 45.9 (35.5–59.3)
Dose-normalized AUC12 h (mg*h/L)b Placebo 41.3 (29.7–57.5) 0.023
Pantoprazole 52.6 (39.9–69.3)
Cmax, mg/L Placebo 8.5 (5.5–13.2) 0.211
Pantoprazole 11.9 (8.4–16.9)
Dose-normalized Cmax, mg/Lb Placebo 9.8 (6.2–15.4) 0.217
Pantoprazole 13.7 (9.5–19.6)
Tmax, h Placebo 3.1 (2.4–4.1) 0.577
Pantoprazole 3.9 (2.7–5.4)
EC-MPS: MPA-G
AUC12 h, mg*h/L Placebo 714.2 (559.2–912.1) 0.274
Pantoprazole 744.6 (571.4–970.4)
Dose-normalized AUC12 h, mg*h/Lb Placebo 818.0 (630.1–1062.0) 0.339
Pantoprazole 852.9 (655.8–1109.3)
Cmax, mg/L Placebo 84.5 (68.6–104.3) 0.159
Pantoprazole 87.6 (68.8–111.7)
Dose-normalized Cmax, mg/Lb Placebo 96.8 (76.8–121.9) 0.192
Pantoprazole 100.4 (78.6–128.2)
Tmax, h Placebo 2.6 (1.8–3.7) 0.180
Pantoprazole 4.3 (3.3–5.7)
Data are expressed as geometric means and 95% CIs, with Wilcoxon signed-rank test used to test the difference between placebo versus pantoprazole for each pharmacoki-
netic parameter. AUC12 h, AUC >12 h, Cmax, peak concentration; Tmax, time to peak concentration.
a
Dose-normalized to 2 g daily (in two equally divided doses) of MMF.
b
Dose-normalized to 1440 mg daily (in two equally divided doses) of EC-MPA.

CNI type. For recipients maintained on MMF and cyclosporin,
MPA-AUC12 h and Cmax and dose-normalized MPA-AUC12 h
and Cmax were reduced by at least 20 and 30%, respectively, with
pantoprazole compared with placebo. For recipients maintained
on MMF and tacrolimus, MPA-AUC12 h and Cmax and dose-
normalized MPA-AUC12 h and Cmax were significantly reduced
by at least 15 and 30%, respectively, with pantoprazole. For
recipients maintained on EC-MPS and either cyclosporin or
tacrolimus, there were no significant changes in MPA-AUC12 h
and Cmax with and without pantoprazole. There were no signifi-
cant differences in MPA-G12 h for recipients maintained on
MMF or EC-MPS and either tacrolimus or cyclosporin 6 panto-
prazole. Figure 3A and B shows the respective boxplots of MPA-
AUC12 h and Cmax of recipients maintained on MMF and EC-
MPS, with placebo or pantoprazole and stratified by CNI type.
Adverse events
There were no serious adverse events during the study period,
with no acute rejection, study drug discontinuation or modifica-
tion of the immunosuppressive medications. A greater propor-
tion of recipients maintained on MMF experienced adverse
events (with placebo and pantoprazole) compared with those

Effect of pantoprazole on MPA exposure 1065

 A MMF + placebo/pantoprazole B EC–MPS + placebo/pantoprazole
18 8
Placebo: geometric mean and 95% CI Placebo: geometric mean and 95% CI
16 Pantoprazole: geometric mean and 95% CI Pantoprazole: geometric mean and 95% CI
7
14
Plasma MPA (mg/L)

Plasma MPA (mg/L)

12
5
10
4
8
3
6
4 2

2 1

0 0
0 0.5 1 1.5 2 3 4 5 6 8 10 12 0 0.5 1 1.5 2 3 4 5 6 8 10 12

Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023

Time (h) Time (h)

FIGURE 2: Plasma MPA concentration–time profiles (geometric means and 95% CI) of recipients maintained on MMF (A) and EC-MPS
R
[MyforticV, (B)]. Co-administration of pantoprazole significantly reduced MPA exposure in recipients maintained on MMF, whereas the MPA
exposure was significantly increased in recipients maintained on EC-MPS.

Table 3. MPA-AUC thresholds in kidney and liver transplant recipients maintained on mycophenolate or EC-MPS with and without pantoprazole

MPA-AUC12 h thresholds, mg*h/L MMF (n ¼ 19) MMF þ pantoprazole (n ¼ 19) EC-MPS (n ¼ 21) EC-MPS þ pantoprazole (n ¼ 21)
>30 17 (89.5) 13 (68.4) 16 (76.2) 17 (81.0)
>40 15 (78.9) 10 (52.6) 10 (47.6) 14 (66.7)
>50 11 (57.9) 8 (42.1) 5 (23.8) 10 (47.6)
>60 10 (52.6) 7 (36.8) 4 (19.0) 9 (42.9)
Data are expressed as n (%).

Table 4. Pharmacokinetic parameters of MPA with concomitant placebo versus pantoprazole in kidney and liver transplant recipients maintained
on MMF or EC-MPS, stratified by calcineurin-inhibitor type (cyclosporin and tacrolimus)

Pharmacokinetic parameters (MMF and EC-MPS) Intervention Geometric means (95% CI)

Cyclosporin Tacrolimus
MMF: MPA
AUC12 h, mg*h/L Placebo 48.1 (34.8–66.5) 58.5 (43.5–78.6)
Pantoprazole 36.9 (26.0–52.4) 49.2 (37.6–64.3)*
Dose-normalized AUC12 h, mg*h/La Placebo 59.3 (41.2–85.3) 91.1 (64.2–129.4)
Pantoprazole 45.5 (28.1–73.7) 76.7 (56.5–104.3) *
Cmax, mg/L Placebo 16.5 (11.5–23.7) 15.9 (10.7–23.4)
Pantoprazole 11.1 (6.8–17.9) 10.5 (7.8–14.2)**
Dose-normalized Cmax, mg/La Placebo 20.4 (14.1–29.5) 24.7 (18.2–33.6)
Pantoprazole 13.6 (7.2–25.9) 16.4 (13.1–20.5)**
EC-MPS: MPA
AUC12 h, mg*h/L Placebo 19.5 (11.3–33.8) 46.2 (33.5–63.6)
Pantoprazole 30.9 (18.6–51.4) 53.8 (40.2–71.8)
Dose-normalized AUC12 h, mg*h/Lb Placebo 20.5 (11.5–36.3) 54.8 (39.5–75.9)
Pantoprazole 32.4 (17.8–58.9) 63.8 (47.8–85.1)
Cmax, mg/L Placebo 3.5 (1.4–8.7) 12.2 (8.0–18.5)
Pantoprazole 9.0 (4.2–19.3) 13.4 (8.7–20.5)
Dose-normalized Cmax, mg/Lb Placebo 3.7 (1.5–9.1) 14.4 (9.4–22.2)
Pantoprazole 9.4 (4.2–21.2) 15.9 (10.4–24.3)
Data are expressed as geometric means and 95% CIs, with Wilcoxon signed-rank test used to test the difference between placebo versus pantoprazole for each pharmacoki-
netic parameter.
a
Dose-normalized to 2 g daily (in two equally divided doses) of MMF.
b
Dose-normalized to 1440 mg daily (in two equally divided doses) of EC-MPA.
*P < 0.05,
**P < 0.01.

1066 A. Sunderland et al.

 A MPA–AUC0-12h: MMF vs. EC–MPS B MPA–Cmax: MMF vs. EC–MPS
(+ pantoprazole/placebo by CNI type) (+ pantoprazole/placebo by CNI type)
MPA AUC-12h (mg*h/L) 150 50

MPA Cmax (mg/L)

40
100
30

20
50
10

0 0
MMF EC–MPS MMF EC–MPS MMF EC–MPS MMF EC–MPS
Tacrolimus Tacrolimus Tacrolimus Cyclosporin
MPA AUC-12h (placebo) MPA AUC-12h (PPI) MPA Cmax (placebo) MPA Cmax (PPI)

Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023

FIGURE 3: Boxplots [showing the median, IQR, minimum and maximum and outliers (represented by solid circle)] of MPA AUC >12 h
R
[MPA-AUC12 h; (A)] and Cmax (B) for recipients maintained on either MMF or EC-MPS (MyforticV), stratified by CNI types (cyclosporin
and tacrolimus), with co-administration with placebo (blue bars) or pantoprazole (red bars).

Table 5. Adverse events of the study population

Adverse events of study cohort MMF (n ¼ 19) EC-MPS (n ¼ 21)

Adverse events Placebo Pantoprazole Placebo Pantoprazole
Any adverse events 8 (42.1) 7 (36.8) 4 (19.0) 2 (9.5)
Gastrointestinal 4 (21.1) 3 (15.6) 2 (9.5) 1 (4.8)
Reflux 2 (10.5) 2 (10.5) 1 (4.8) 1 (4.8)
Diarrhoea 1 (5.3) 1 (5.3) 0 (0.0) 0 (0.0)
Abdominal pain 1 (5.3) 1 (5.3) 0 (0.0) 1 (4.8)
Nausea/vomiting 1 (5.3) 1 (5.3) 1 (4.8) 0 (0.0)
Infection 2 (10.5) 3 (15.6) 0 (0.0) 0 (0.0)
Respiratory 1 0 0 0
Urinary tract 0 2 0 0
Others 1 0 0 0
Hospitalization 0 (0.0) 1 (5.3)b 0 (0.0) 0 (0.0)
Miscellaneous 2 (10.5) 1 (5.3) 3 (14.3) 0 (0.0)
Headache 1 1 1 0
Skin rash 1 0 0 0
Others 0 0 2 0
Haematology/biochemistrya
Creatinine, lmol/L 129 (80–154) 127 (80–161) 121 (91–138) 114 (85–149)
eGFR, mL/min/1.73 m2 50 (38–85) 49 (35–71) 56 (47–75) 54 (46–87)
White cell count (109/L) 6 (6–8) 4 (4–7) 7 (6–8) 7 (6–9)
Haemoglobin, g/L 130 (112–140) 128 (115–141) 138 (126–152) 137 (123–152)
Albumin, g/L 39 (38–42) 40 (38–42) 40 (38–43) 41 (38–42)
Allograft outcomes Placebo Pantoprazole Placebo Pantoprazole
Acute rejection 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Allograft failure 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Death 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Data are expressed as n (%).
a
Expressed as median (IQR).
b
Hospitalization secondary to urinary tract infection and dehydration.

maintained on EC-MPS, and the majority of adverse events were on placebo and pantoprazole, regardless of whether they were
mild non-specific symptoms (headache and/or mild gastro- maintained on MMF or EC-MPS. There were no significant dif-
intestinal symptoms). The proportion of recipients who had ex- ferences in serum haemoglobin, albumin or creatinine (and
perienced reflux symptoms was similar for recipients maintained eGFR) between the two pharmacokinetic timepoints in either

Effect of pantoprazole on MPA exposure 1067

group of recipients maintained on MMF or EC-MPS. Table 5
shows the adverse events for recipients maintained on MMF and
EC-MPS, stratified by placebo and pantoprazole.
Sensitivity analysis
In the sensitivity analysis excluding the one liver transplant
recipient (of recipients maintained on MMF), the geometric
means (95% CI) of each pharmacokinetic parameter in the
presence of placebo and pantoprazole had remained similar
(Supplementary data, Table S1). When the study population
was stratified according to eGFR thresholds of 60 and
>60 mL/min/1.73 m2, the estimates for actual and dose-
normalized MPA and MPA-G AUC12 h and Cmax were similar
to the estimates from the main analysis for recipients main-
tained on MMF and EC-MPS, although statistically significant
difference in the change between MPA-AUC12 h and/or Cmax in
the presence of placebo versus pantoprazole was evident only
for recipients with eGFR of 60 mL/min/1.73 m2. In recipients
with eGFR of >60 mL/min/1.73 m2, the proportional change in
MPA-AUC12 h and Cmax was not statistically significant but was
similar to recipients with eGFR of 60 mL/min/1.73 m2
(Supplementary data, Table S2).
DISCUSSION
This randomized, double-blind placebo-controlled cross-over
study showed an important interaction between pantoprazole
and MPA formulations in stable kidney and liver transplant
recipients maintained on CNI-based immunosuppression.
Consistent with the known increase in gastric pH with the use
of PPI, co-administration of pantoprazole reduced the bioavail-
ability of MPA in patients maintained on MMF but had an en-
hanced effect on the MPA bioavailability in those maintained
on EC-MPS.
The pharmacokinetic profiles of the two MPA formulations
of MMF and EC-MPS are dissimilar, with the absorption re-
quiring an acidic and neutral pH environment, respectively, be-
fore making active MPA available. As such, MPA
concentrations peak relatively earlier, within 1–2 h, following
MMF administration. In contrast, peak MPA concentrations
occur between 2 and 4 h after EC-MPS [15–17]. Consequently,
it has been shown that PPI, by suppressing gastric acid secretion
will interfere with the absorption and reduce the total MPA ex-
posure following MMF but not EC-MPS. In two randomized
cross-over studies (not placebo-controlled) of healthy volun-
teers, concomitant PPI treatment (n ¼ 12 omeprazole 20 mg
twice daily and n ¼ 12 pantoprazole 40 mg twice daily) signifi-
cantly reduced the MPA and MPA-G AUC12 h and Cmax with
MMF but not with EC-MPS [10, 18]. In both studies, the volun-
teers were exposed only to a single daily dose of MMF (1 g) and
EC-MPS (720 mg). In a randomized 4  4 cross-over single-
centre German study (2-week periods each of MMF, EC-MPS,
EC-MPS/pantoprazole and MMF/pantoprazole) of 18 kidney
transplant recipients maintained on cyclosporin-based regimen,
there was at least a respective 10 and 20% reduction in MPA-
AUC12 h and Cmax when MMF was co-administered with pan-
toprazole, but this was not statistically significant. Pantoprazole
1068
resulted in a significant earlier Tmax when co-administered with
EC-MPS, but there was no effect on MPA-AUC12 h or Cmax
[19]. Given the small number of recipients and the large inter-
individual pharmacokinetic variability, the true effect of PPI on
MPA exposure remains uncertain. Similarly, PPI-induced re-
duction in MPA exposure in 22 heart transplant recipients
maintained on MMF has been reported [8], but a similar effect
was not observed for heart or lung recipients maintained on
EC-MPS (n ¼ 21) [9]. Similarly, in a retrospective study of 61
kidney transplant recipients, lansoprazole reduced the MPA ex-
posure in recipients maintained on MMF and tacrolimus, but
this work left open the possibility that the drug–drug interac-
tion may be dependent on the PPI type and cytochrome P450
and efflux transporter genetic polymorphisms (e.g. CYP2C19
Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023
and ABCB1 polymorphisms) [20]. Nevertheless, these studies
were not randomized controlled trials and therefore the clinical
significance of the study findings must be interpreted with cau-
tion. In our study, co-administration of pantoprazole with
MMF significantly reduced the total MPA exposure (MPA-
AUC12 h and Cmax), which was not observed in recipients main-
tained on EC-MPS. However, pantoprazole had no effect on
MPA Tmax or the pharmacokinetic profile of MPA-G (which
should reflect the total amount of absorbed MPA) in recipients
maintained on MMF or EC-MPS, which may reflect the large
inter-patient variability, potential differences polymorphisms of
uridine 50 -diphospho-glucuronosyltransferase genes (enzymes
involved in the metabolism of MPA), the pre-specified sam-
pling points to calculate the pharmacokinetic profile may have
missed the true Cmax, and the potential variability in the renal
excretion and the entero-hepatic recycling of MPA-G [21, 22].
The finding that pantoprazole significantly increased the MPA-
AUC12 h and dose-normalized AUC12 h following EC-MPS ad-
ministration suggests that absorption of EC-MPS occurred ear-
lier in the presence of pantoprazole even though the Cmax
attained was not dissimilar to the absence of pantoprazole.
Nevertheless, it has been shown that the MPA pharmacokinetic
profile for EC-MPS exhibits a greater intra-patient variability
when compared with MMF formulation, which may have con-
tributed to differences between our study and previous reports
[23]. Differences in the study design, sample size, population
characteristics and concomitant CNI maintenance may also
have contributed to the dissimilar findings between our study
and the cross-over study from Germany [19].
The systemic exposure of MMF and EC-MPS has been
shown to be generally equivalent after equimolar dosing (i.e.
MPA-AUC0–1 following 720 mg EC-MPS is equivalent to 1 g
of MMF: 66.5 lg*h/mL versus 63.7 lg*h/mL, respectively) [16,
21]. Several randomized controlled trials and cohort studies
have shown that higher MPA exposure (MMF formulation)
may be associated with a lower risk of acute rejection, particu-
larly achieving MPA-AUC >30 mg*h/L in the first week post-
transplant, but this association was no longer apparent beyond
this timepoint [4, 5, 24–27]. The clinical relevance of MPA con-
centration in the outcome of other solid organ transplants (in-
cluding liver and heart transplant recipients) remains unclear,
with most studies evaluating MPA trough levels rather than ex-
tended MPA profiles [28–32]. There have been no clinical
A. Sunderland et al.
studies that have examined the association between MPA expo-
sure and allograft outcome in kidney transplant recipients
maintained on EC-MPS. In our study, a greater proportion of
recipients maintained on MMF had achieved higher mean
MPA-AUC12 h, despite a smaller proportion being maintained
on the ‘maximal bio-equivalent dose’ of MMF (2 g/day, 32%)
compared with EC-MPS (1440 mg/day, 52%). In the presence
of pantoprazole, the proportion of recipients maintained on
MMF with MPA-AUC12 h >30 mg*h/L was reduced by 22%
compared with placebo, which may have potential clinical rele-
vance in the early post-transplant period. For recipients main-
tained on EC-MPS, pantoprazole substantially increased the
proportion of recipients achieving higher MPA-AUC12 h
thresholds, particularly >40 mg*h/L.
Co-administration of different CNI types has been shown to
influence MPA exposure with the use of cyclosporin being associ-
ated with up to 50% reduction in MPA exposure compared with
tacrolimus. This has been attributed to the differential effect of
the different CNIs on enterohepatic recycling [21, 33, 34]. In our
study, the MPA-AUC12 h and dose-normalized AUC12 h were
higher for tacrolimus-treated patients compared with
cyclosporin-treated patients, despite a higher median dose of
MMF and EC-MPS being prescribed for cyclosporin-treated
patients. The co-administration of pantoprazole reduced the
MPA-AUC12 h and Cmax for tacrolimus- and cyclosporin-treated
patients, but this was not statistically significant (with wide CIs)
in the latter group, likely reflecting the small number of patients
maintained on cyclosporin. Similarly, when stratified by eGFR of
thresholds of 60 and >60 mL/min/1.73 m2, the results were
similar although the proportional change in MPA-AUC12 h and
Cmax was not statistically significant for recipients with entry
eGFR of >60 mL/min/1.73 m2, likely to reflect the smaller sample
size.
There are a few limitations in this study. Our sample size cal-
culation was based on an effect size of 25% in AUC12 h, and
when combined with the variability in MPA pharmacokinetic
profiles may suggest that our study was not sufficiently powered
for certain pharmacokinetic parameters, particularly when
stratified by CNI types. Nevertheless, this study remains the
largest randomized cross-over trial conducted in stable kidney
and liver transplant recipients. It is possible that the 1 week
washout period for pantoprazole was inadequate, but given the
plasma half-life of pantoprazole is around 1 h [35], it is unlikely
that there was any residual carry-over effect of pantoprazole
during the wash-out period. In addition, the dose of 40 mg daily
of pantoprazole was chosen as the intervention to reflect regi-
mens most commonly used in clinical transplant practice in
Australia, but the study findings may not be able to extrapolate
to other PPIs, which may have dissimilar half-lives and inhibi-
tory effects on gastric acid secretion [36]. Given, we had only
recruited one liver transplant recipient, our findings cannot be
extrapolated to this population. Furthermore, our study find-
ings may not be readily generalizable across kidney transplant
recipients with poorer allograft function or in recipients with
long-term exposure to PPI.
Despite the pharmacokinetic variability of MPA, the concur-
rent administration of PPI substantially reduced the MPA
Effect of pantoprazole on MPA exposure
concentrations by almost 20%, but the longer term clinical ef-
fect of this interaction remains unknown. Even though the clin-
ical significance of MPA TDM in chronic kidney and liver
transplant recipients remains uncertain, clinicians should still
be cognizant of this important drug interaction when prescrib-
ing PPI with MMF or EC-MPS in the early post-transplant pe-
riod. Future studies designed to evaluate the allograft outcome
of recipients maintained on different MPA formulation with
and without PPI are needed to ascertain the long-term clinical
relevance of this drug interaction.
SUPPLEMENTARY DATA
Supplementary data are available at ndt online.
Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023
ACKNOWLEDGEMENTS
The authors are grateful for the unrestricted educational grant
R
provided by NovartisV for the completion of this trial; how-
ever, the study design, conduct of the trial, interpretation of
the data, analysis, writing of the paper and decision to submit
the manuscript for publication were undertaken only by the
R
authors, without involvement by NovartisV.
FUNDING
W.H.L. is supported by a Clinical Research Fellowship from
the Raine Foundation (University of Western Australia and
Health Department of Western Australia) and Jacquot
Research Foundation (Royal Australasian College of
Physicians). G.W. is supported by a National Health and
Medical Research Council Career Development Fellowship.
E.O. is supported by a National Heart Foundation Future
Leader Fellowship (Award ID: 102538).
AUTHORS’ CONTRIBUTIONS
W.H.L. and G.R. designed the study and recruited the partici-
pants. W.H.L. has full access to the trial data. W.H.L. and
E.O. participated in the analysis of the data. All authors
participated in the interpretation of the data and writing of
the article.
CONFLICT OF INTEREST STATEMENT
N.B. has received speaking honoraria from Baxter, travel
grants from Amgen and Roche, and unrestricted educational
grants from Amgen, Roche and Baxter. W.H.L. has received
speaking honoraria from Alexion, Astellas and Novartis, and
unrestricted educational grants from Astellas and Novartis.
REFERENCES
1. Ekberg H, Tedesco-Silva H, Demirbas A et al. Reduced exposure to calci-
neurin inhibitors in renal transplantation. N Engl J Med 2007; 357:
2562–2575
2. Le Meur Y, Buchler M, Thierry A et al. Individualized mycophenolate mofe-
til dosing based on drug exposure significantly improves patient outcomes
after renal transplantation. Am J Transplant 2007; 7: 2496–2503
1069
 3. Knight SR, Morris PJ. Does the evidence support the use of mycophenolate
mofetil therapeutic drug monitoring in clinical practice? A systematic re-
view. Transplantation 2008; 85: 1675–1685
4. Gaston RS, Kaplan B, Shah T et al. Fixed- or controlled-dose mycophenolate
mofetil with standard- or reduced-dose calcineurin inhibitors: the Opticept
trial. Am J Transplant 2009; 9: 1607–1619
5. van Gelder T, Silva HT, de Fijter JW et al. Comparing mycophenolate mofe-
til regimens for de novo renal transplant recipients: the fixed-dose concen-
tration-controlled trial. Transplantation 2008; 86: 1043–1051
6. Helderman JH, Goral S. Gastrointestinal complications of transplant immu-
nosuppression. J Am Soc Nephrol 2002; 13: 277–287
7. Kofler S, Deutsch MA, Bigdeli AK et al. Proton pump inhibitor co-
medication reduces mycophenolate acid drug exposure in heart transplant
recipients. J Heart Lung Transplant 2009; 28: 605–611
8. Kofler S, Shvets N, Bigdeli AK et al. Proton pump inhibitors reduce myco-
phenolate exposure in heart transplant recipients-a prospective case-
controlled study. Am J Transplant 2009; 9: 1650–1656
9. Kofler S, Wolf C, Shvets N et al. The proton pump inhibitor pantoprazole
and its interaction with enteric-coated mycophenolate sodium in transplant
recipients. J Heart Lung Transplant 2011; 30: 565–571
10. Rupprecht K, Schmidt C, Raspe A et al. Bioavailability of mycophenolate
mofetil and enteric-coated mycophenolate sodium is differentially affected
by pantoprazole in healthy volunteers. J Clin Pharmacol 2009; 49:
1196–1201
11. Westley IS, Sallustio BC, Morris RG. Validation of a high-performance
liquid chromatography method for the measurement of mycophenolic
acid and its glucuronide metabolites in plasma. Clin Biochem 2005; 38:
824–829
12. Hale MD, Nicholls AJ, Bullingham RE et al. The pharmacokinetic-
pharmacodynamic relationship for mycophenolate mofetil in renal trans-
plantation. Clin Pharmacol Ther 1998; 64: 672–683
13. van Gelder T, Hilbrands LB, Vanrenterghem Y et al. A randomized double-
blind, multicenter plasma concentration controlled study of the safety and
efficacy of oral mycophenolate mofetil for the prevention of acute rejection
after kidney transplantation. Transplantation 1999; 68: 261–266
14. van Gelder T, Le Meur Y, Shaw LM et al. Therapeutic drug monitoring of
mycophenolate mofetil in transplantation. Ther Drug Monit 2006; 28:
145–154
15. Bullingham RE, Nicholls AJ, Kamm BR. Clinical pharmacokinetics of
mycophenolate mofetil. Clin Pharmacokinet 1998; 34: 429–455
16. Arns W, Breuer S, Choudhury S et al. Enteric-coated mycophenolate so-
dium delivers bioequivalent MPA exposure compared with mycophenolate
mofetil. Clin Transplant 2005; 19: 199–206
17. Lidgate D, Brandl M, Holper M et al. Influence of ferrous sulfate on the sol-
ubility, partition coefficient, and stability of mycophenolic acid and the ester
mycophenolate mofetil. Drug Dev Ind Pharm 2002; 28: 1275–1283
18. Kees MG, Steinke T, Moritz S et al. Omeprazole impairs the absorption of
mycophenolate mofetil but not of enteric-coated mycophenolate sodium in
healthy volunteers. J Clin Pharmacol 2012; 52: 1265–1272
19. Rissling O, Glander P, Hambach P et al. No relevant pharmacokinetic inter-
action between pantoprazole and mycophenolate in renal transplant patients:
a randomized crossover study. Br J Clin Pharmacol 2015; 80: 1086–1096
20. Miura M, Satoh S, Inoue K et al. Influence of lansoprazole and rabeprazole
on mycophenolic acid pharmacokinetics one year after renal transplanta-
tion. Ther Drug Monit 2008; 30: 46–51
1070
21. Shaw LM, Figurski M, Milone MC et al. Therapeutic drug monitoring of
mycophenolic acid. Clin J Am Sci Nephrol 2007; 2: 1062–1072
22. Levesque E, Delage R, Benoit-Biancamano MO et al. The impact of
UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharma-
cokinetic profile of mycophenolic acid after a single oral dose in healthy vol-
unteers. Clin Pharmacol Ther 2007; 81: 392–400
23. Cattaneo D, Cortinovis M, Baldelli S et al. Pharmacokinetics of mycopheno-
late sodium and comparison with the mofetil formulation in stable kidney
transplant recipients. Clin J Am Sci Nephrol 2007; 2: 1147–1155
24. Pawinski T, Durlik M, Szlaska I et al. Comparison of mycophenolic acid
pharmacokinetic parameters in kidney transplant patients within the first 3
months post-transplant. J Clin Pharm Ther 2006; 31: 27–34
25. Sanchez Fructuoso AI, de la Higuera MA, Garcia-Ledesma P et al. Graft
outcome and mycophenolic acid trough level monitoring in kidney trans-
plantation. Transplant Proc 2009; 41: 2102–2103
26. Sanchez-Fructuoso AI, de la Higuera MA, Giorgi M et al. Inadequate myco-
phenolic acid exposure and acute rejection in kidney transplantation.
Downloaded from https://academic.oup.com/ndt/article/35/6/1060/5855235 by guest on 06 November 2023
Transplant Proc 2009; 41: 2104–2105
27. Gourishankar S, Houde I, Keown PA et al. The CLEAR study: a 5-day,
3-g loading dose of mycophenolate mofetil versus standard 2-g
dosing in renal transplantation. Clin J Am Sci Nephrol 2010; 5:
1282–1289
28. Saliba F, Rostaing L, Gugenheim J et al. Corticosteroid-sparing and optimi-
zation of mycophenolic acid exposure in liver transplant recipients receiving
mycophenolate mofetil and tacrolimus: a randomized, multicenter study.
Transplantation 2016; 100: 1705–1713
29. Meiser BM, Pfeiffer M, Schmidt D et al. Combination therapy with tacroli-
mus and mycophenolate mofetil following cardiac transplantation: impor-
tance of mycophenolic acid therapeutic drug monitoring. J Heart Lung
Transplant 1999; 18: 143–149
30. Yamani MH, Starling RC, Goormastic M et al. The impact of routine myco-
phenolate mofetil drug monitoring on the treatment of cardiac allograft re-
jection. Transplantation 2000; 69: 2326–2330
31. Tredger JM, Brown NW, Adams J et al. Monitoring mycophenolate in liver
transplant recipients: toward a therapeutic range. Liver Transpl 2004; 10:
492–502
32. Kuypers DR, Le Meur Y, Cantarovich M et al. Consensus report on thera-
peutic drug monitoring of mycophenolic acid in solid organ transplanta-
tion. Clin J Am Sci Nephrol 2010; 5: 341–358
33. van Gelder T, Klupp J, Barten MJ et al. Comparison of the effects of tacroli-
mus and cyclosporine on the pharmacokinetics of mycophenolic acid. Ther
Drug Monit 2001; 23: 119–128
34. Grinyo JM, Ekberg H, Mamelok RD et al. The pharmacokinetics of myco-
phenolate mofetil in renal transplant recipients receiving standard-dose or
low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus: the
Symphony pharmacokinetic substudy. Nephrol Dial Transplant 2009; 24:
2269–2276
35. Huber R, Hartmann M, Bliesath H et al. Pharmacokinetics of pantoprazole
in man. Int J Clin Pharmacol Ther 1996; 34: 185–194
36. Shin JM, Sachs G. Pharmacology of proton pump inhibitors. Curr
Gastroenterol Rep 2008; 10: 528–534
Received: 30.1.2020; Editorial decision: 31.3.2020
A. Sunderland et al.