Venkata Raman An 1995

C~n . Phormocokinet. 29 (6): 404-430.
1995
DRUG DISPOSITION 0312-5963/95/00 12-()4()4/S 13.50/0
© Adis International limited. All rights reserved.
Clinical Pharmacokinetics of
Tacrolimus
Raman Venkataramanan},3 Arun Swaminathan,1 Tata Prasad,1 Ashok Jain,2 Sheila
Zuckerman,3 Vijay Warty,3 John McMichael,3 Jacqueline Lever} Gilbert Burckart4 and
Thomas Starz[2
1 Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh,
Pittsburgh, Pennsylvania, USA
2 Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh,
Pennsylvania, USA
3 Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh,
Pennsylvania, USA
4 Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh,
Pittsburgh, Pennsylvania, USA
Contents
Summary .... . . . . . . . . 405
1. Dosage Forms of Tacrolimus . 405
2. Analytical Methodology .. · 406
2.1 Enzyme Immunoassays . · 406
2.2 Radioreceptor Assay . . · 407
2.3 Chromatographic/Moss Spectrometric Methods · 408
2.4 Bioassay .. .. . . . . . . · 409
2.5 Comparison of Methods . . 409
2.6 The Matrix Effect · 410
3. Pharmacokinetics . . . . . . . · 410
3.1 Absorption . . . . . . . . . .411
3.2 Distribution and Protein Binding . · 412
3.3 Metabolism . . . . . . . . . . . .414
3.4 Excretion . . . . . . . . . . . . . . . . 416
3,5 Pharmacokinetic Parameters . . . · 417
4. Factors Affecting Tacrolimus Pharmacokinetics · 418
5. Drug Interactions , . . . . . . . . . , , . 419
6, Treatment of Drug Toxicity/Overdose · 421
7. Therapeutic Monitoring of Tacrolimus · 421
7.1 Rationale for Monitoring .. , , . · 421
7.2 Trough Concentration Monitoring · 423
7.3 Methods/Matrix for Monitoring Tacrolimus . 423
7.4 Frequency of Tacrolimus Monitoring · 424
7.5 Precautions .. . .. , 424
8. Dosage Regimen Design , 424
9. Conclusions . . . . . . . . , 425
Tacrolimus Clinical Pharmacokinetics 405
Summary Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive

properties, is currently available as an intravenous formulation and as a capsule
for oral use, although other formulations are under investigation.
Tacrolimus concentrations in biological fluids have been measured using a
number of methods, which are reviewed and compared in the present article. The
development of a simple, specific and sensitive assay method for measuring
concentrations of tacrolimus is limited by the low absorptivity of the drug, low
plasma and blood concentrations, and the presence of metabolites and other drugs
which may interfere with the determination of tacrolimus concentrations. Cur-
rently, most of the pharmacokinetic data available for tacrolimus are based on an
enzyme-linked immunosorbent assay method, which does not distinguish
tacrolimus from its metabolites.
The rate of absorption of tacrolimus is variable with peak blood or plasma
concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral
dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a
mean blood to plasma ratio of about 15; albumin and (XI-acid glycoprotein appear
to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised
prior to elimination. The mean disposition half-life is 12 hours and the total body
clearance based on blood concentration is approximately 0.06 L/hlkg. The elim-
ination of tacrolimus is decreased in the presence of liver impairment and in the
presence of several drugs.
Various factors that contribute to the large inter- and interindividual variability
in the pharmacokinetics of tacrolimus are reviewed here. Because of this vari-
ability, the narrow therapeutic index of tacrolimus, and the potential for several
drug interactions, monitoring of tacrolimus blood concentrations is useful for
optimisation of therapy and dosage regimen design.
Tacrolimus (FK506) is a macrocyclic lactone alkaline conditions. At the present time, these prop-
(fig. 1) with potent immunosuppressive proper- erties make it difficult to formulate tacrolimus into
ties)') It has been in clinical use in Japan since an ideal dosage form for patient use.
1993, and was approved in the US in April 1994
for the prophylaxis of organ rejection after liver
12
transplantation. Tacrolimus is also effective in pre- H3CO
venting graft rejection in heart, small bowel and
H3CO ·.•. 0
kidney transplant recipients. [2.3) The role of 15
tacrolimus therapy in several autoimmune diseases
V
H3C·· ..
N 4
is currently being evaluated. 2 3
Tacrolimus is a very lipophilic compound with 18 CH3#
a molecular weight of 804, existing as a monohy-
20
drate in the solid state. It is highly soluble in meth-
anol , chloroform, acetone and ethyl acetate, soluble
in ethyl ether, propylene glycol and polyethylene
o
glycol, but insoluble in water and n-hexane.[4)
Tacrolimus is stable in the solid state, in methanol
and in mildly acidic media, but tends to degrade under Fig. 1. Structure of tacrolimus.
© Adis International Limited. All rights reserved. Clin. Pharmacokinet. 29 (6) 1995
406 Venkataramanan et al.
1. Dosage Forms of Tacrolimus fluids have been measured using a number of meth-
ods (table I). However, the development of a sim-
Tacrolimus is currently available for intrave- ple, specific and sensitive assay method for measur-
nous administration as a solution containing tac- ing tacrolimus in biological fluids is limited by:
rolimus, alcohol and a surfactant (HCO-16). The • the low absorptivity of tacrolimus
potential for anaphylactic reactions due to the pre- • the low concentrations of tacrolimus in plasmal
sence of a surfactant in the intravenous formulation blood, and
should be borne in mind while using this formula- • the presence of several other drugs in the blood
tion in patients. The intravenous formulation (5 samples obtained from transplant patients, which
mg/ml) must be diluted in 5% dextrose or normal potentially interfere with the analysis of tacro-
saline and administered as a continuous infusion limus.
over 24 hours to minimise the nephrotoxicity of the The analytical methods available for measuring
drug. When diluted in dextrose or normal saline, tacrolimus in biological fluids have been sum-
tacrolimus is stable for at least 24 hours and is com- marised previously,l32,491 The currently available
pletely available from (i.e. not adsorbed onto) plastic assays can be broadly classified as enzyme immu-
syringes, glass and polyolefin containers.l 51 Certain noassays, a radioreceptor assay, chromatographic/
intravenous administration sets, such as Venoset mass spectrometric assays and a bioassay.
and Accuset, can adsorb significant amounts of
tacrolimus from the intravenous solution and their 2.1 Enzyme Immunoassays
use may lead to a lower dose of tacrolimus being
delivered to patients.l6] The oral dosage form of In 1987, Tamura et aU121 reported the first
tacrolimus is available as Img and 5mg capsules method for quantitation of tacrolimus in plasma
of a solid dispersion of tacrolimus in hydroxy- using an enzyme-linked immunosorbent assay
propylmethylcellulose. (ELISA) method following a solid-phase extrac-
Several additional formulations are currently tion procedure to separate tacrolimus from other
being evaluated. A liposomal tacrolimus formula- components in the sample. The clinical application
tion has been reported to provide better immuno- of this assay was first reported in 1990,(13) and a
suppression in rats, compared with the currently modification of this method has been used to mea-
available intravenous formulation, in spite of sure tacrolimus in whole blood.l 14 ,34) A unified
achieving similar blood concentrations of tacro- method of extraction of whole blood and plasma
limusp,8)It has been suggested that it may also be using methylene chloride was reported by
less nephrotoxic and neurotoxic than the currently Kobayashi et al. in 1991,(16) while ethyl acetate has
available intravenous formulation, because of re- also been used for the extraction of tacrolimus from
duced accumulation of tacrolimus in the kidney blood, tissue and plasma,l351 Although the results
and the brain of rats treated with the liposomal for- obtained after methylene chloride extraction and
mulation. Another liposomal formulation with the solid-phase extraction procedures correlate
good in vitro stability, prolonged disposition and well with each other (r2 = 0.91), the solid-phase
immunosuppressive activity similar to that of free extraction method consistently yields higher esti-
drug has also been reported)91 mates (about 42%), in comparison with the proce-
dure that uses methylene chloride for extraction.l 161
2. Analytical Methodology A number of drugs (see table II) used to treat
transplant patients do not appear to cross-react with
Tacrolimus is stable in whole blood specimens the antibody used in the ELISA procedure.[14-161
for about 1 year at -70'C, for at least 2 weeks at The IncStar PRO-TRAC@ ELISA method that
4'C and 22°C,[101 and for at least 2 to 3 days at uses the same anti-FK506 monoclonal antibody as
37'C.l111 Tacrolimus concentrations in biological that used in the ELISA method described above
Table I. Analytical methods for measuring tacrolimus

Assay Biological Extraction Detection Sample Periormance Linearity" Reproducibilityb Reference
fluid volume (~I) time (h) (mg/L) intraday interday
ELISA Plasma Benzene Colourimetric 100 0.02-10 12 23 12
ELISA Plasma Solid phase Colourimetric 100 24 0.1-5 27 13
ELISA Plasma Solid phase Colourimetric 100 8 O.HO 7 17 14
ELISA Plasma Liquid Colourimetric 100 8 O.HO 11 16
ELISA Plasma Liquid Colourimetric 300 8 O.HO 8 23 17
ELISA Plasma Liquid Colourimetric 300 24 0.2-10 11 16 18
ELISA Plasma Liquid Colourimetric 100 8 0.1-8 17 19
ELISA Blood Solid phase Colourimetric 25 8 0.8-80 13 14 14
ELISA Blood Solid phase Colourimetric 25 6 3-75 8 16 15
ELISA Blood Liquid Colourimetric 25 8 0.8-64 13 19
ELISA Blood Liquid Colourimetric 20 24 1.0-120 18 21 18
ELISA Blood Liquid Colourimetric 20 24-30 2-80 10 14 21
ELISA Blood Solid Colourimetric 50 8 0.5-50 21 28 20
phaselliquid
MEIAlIMX Blood No extraction Colourimetric 100 0.75 5-60 11.8 22
MEIAlIMX Blood No extraction Colourimetric 100 0.6 5-60 10 16 21
MEIAlIMX Blood No extraction Colourimetric 100 0.75 10-70 23
MEIAlIMX Blood No extraction Colourimetric 100 5-60 9 15 20
HPLC-ELISA Serum Solid phase Colourimetric 200 24 0.1- 12 29 24
HPLC-ELISA Plasma Solid phase/ Colourimetric 200 24 0.1-10 17 25
HPLC
HPLC-ELISA Blood Solid phase/ Colourimetric 200 24 0.8-64.0 14 19
HPLC
HPLC-CL Plasma Liquid/solid Derivatisation 100 24 5-1000 8 8 26
phase
HPLC-MS Blood Solid phase/ MS 1000 24 0.25-225 11 12 27
HPLC
Bioassay Plasma PLT-inhibition 100 72 0.02-0.1 <5.0 28
Radio receptor Blood Solid phase Radioactivity 200 6 1-25 9 9 29
ELISA Blood Methanol Colourimetric 25 4 0.5-60 11 15 30
HPL-fluorescent Blood Liquid/HPLC Fluorescence 1000 24 0.5-200 11.5 31
a Lower end of linearity range is accepted as the minimum detectable quantity.
b Highest coefficient of variation of this assay reported rounded to a whole number.
Abbreviations: CL =chemiluminescence; ELISA =enzyme-linked immunosorbent assay; HPLC =high periormance liquid chromatography;
MEIAIIMX =microparticulate enzyme immunoassayllMX analyser (Abbott); MS =mass spectrometry; PLT-inhibition =inhibition of primed
lymphocyte response.
produces results which are essentially equivalent Abbott, that measures the concentrations of
to the microparticulate enzyme immunoassay tacrolimus in whole blood has been reported. [22]
(MEIA) method (see below»)34J It is more sensitive This method is not sufficiently sensitive to mea-
than the MEIA method, but requires more time to sure low blood concentrations of tacrolimus, and
perform. [30J is also not completely specific to tacrolimus; a
A semi-automated technique, based on the prin- more sensitive MEIA assay is currently under eval-
ciple of MEIA for the IMX analyser developed by uation. However, the existing MEIA method is
Table II. Drugs which do not appear to cross-react with the antibody evaluated. The trough plasma or blood tacrolimus
used in enzyme-linked immunosorbent assay (ELlSA)114'16)
concentrations as determined by ELISA and
Amikacin Netilmicin
HPLC-ELISA are similar in patients with normal
Amphotericin B Nifedipine
Azathioprine Paracetamol (acetaminophen) liver function and in patients with variable kidney
Carbamazepine Phenobarbital (phenobarbitone) function, indicating the lack of accumulation of
Cyclosporin Phenytoin
Digitoxin Prednisolone
any metabolites cross-reacting with the antibody
Digoxin Primidone used in the assay in plasma/blood of these pa-
Disopyramide Procainamide tients.[14] The HPLC-ELISA procedures have,
Erythromycin Quinidine
Ethosuximide Salicylates
however, identified the presence of component(s)
Flecainide Theophylline that cross-react with the antibody used in the
Fluconazole Tobramycin ELISA in the serum of several paediatric liver trans-
Gentamycin Valproic acid
Lidocaine (lignocaine) Vancomycin plant patients[24] and in the plasma of adult liver
Methylprednisolone transplant patients with poor liver function ,l 14]
Recently, an HPLC-MEIAassay has been devel-
oped to measure blood tacrolimus concentra-
rapid and simple, and an interlaboratory quality as-
tions,l 361 This method involves chromatographic
surance programme has been established to ensure
separation of the various components in the blood
consistency of data generated from different trans-
plant centres.[17.18] extract, followed by the application of MEIA to
quantitate tacrolimus in the fraction isolated.
2.2 Radioreceptor Assay Tacrolimus concentrations in renal and liver trans-
plant patients measured by the direct MEIA method
In the radioreceptor assay, tacrolimus extracted have been reported to be 19 to 48% higher than
from the blood sample competes with tritiated the concentrations measured by the HPLC-MEIA
dihydro-tacrolimus for binding to a partially puri- method, indicating a significant cross-reactivity of
fied preparation of FK binding protein (FKBP),l291 some of the metabolites of tacrolimus in the blood
This assay is simple to perform, requires a small samples with the antibody used in the MEIA assay.
volume of blood and can provide a rapid turn- An HPLC assay method with chemilumines-
around time. The results of this assay correlate well cence detection (derivatisation with dansyl hydra-
with whole blood ELISA assay (r2 = 0.97). How- zine) to measure the concentration oftacrolimus in
ever, consistently higher tacrolimus concentrations serum and lymph of rats has been reported.[ 261This
are estimated by this assay in comparison with the method requires a column-switching system for
ELISA, indicating that the assay is nonspecific. It HPLC, and is not readily reproducible. A modifi-
is not clear whether the affinity of a molecule to- cation of this method (liquid extraction and on-col-
wards FKBP is related to the immunosuppressive umn clean up) with fluorescent detection has been
activity of that molecule. Any further development
recently reported for the measurement of tacro-
of the radio receptor assay depends on establishing
limus in whole blood samples.[3)]
a relationship between the factors mentioned above.
An HPLC-mass spectrometric (HPLC-MS)
method for measuring tacrolimus and its metabo-
2.3 Chromatographic/Mass Spectrometric
lites in patient's blood, bile and urine samples is
Methods
also available.[27.37.381 This method involves solid-
In order to improve the specificity of the ELISA, phase extraction of the biological samples and the
a solid-phase extraction and a high performance use of HPLC to separate various components, fol-
liquid chromatographic (HPLC) separation and lowed by the use of a mass spectrometer as a de-
fractionation of various components in the biolog- tector. While the HPLC-MS assay is highly spe-
ical fluid prior to the application of ELISA has been cific and sensitive, the lack of routine availability
Table III. Comparison of different methods of measuring tacrolimus

Methods Matrix Transplant r2 Conversion factor Temperature No. of Reference
population y= mx+b separation (C) specimens
SP vsMC Plasma Kidney, liver 0.91 y = 1.4x + 0.4 37 40 16
MC vsSP Plasma Kidney, liver 0.94 y = 0.9x + 0.07 37 80 25
MC vsSP Plasma Liver 0.41 y =0.08x + 0.08 24 20 20
MC vsSP Blood Liver 0.79 y = 0.6x + 2.0 20 20
MC vsHPLC Plasma Liver 0.85 y= 1.75x-0.03 37 39 19
SP vsHPLC Plasma Liver 0.89 y= 1.87x + 0.14 37 39 19
MC vsHPLC Plasma Kidney 0.92 y = 0.92x + 0.27 37 44 19
SP vsHPLC Plasma Kidney 0.82 y= 1.0x + 0.25 37 44 19
MC vsHPLC Blood Liver 0.90 y = 1.0x+ 0.83 40 19
SP vsHPLC Blood Liver 0.85 y = 0.9x + 1.5 40 19
MC vsHPLC Blood Kidney 0.82 y = 1.1x vs 1.8 38 19
SP vsHPLC Blood Kidney 0.95 y = 0.9x + 3.7 45 19
MC vslMX Blood Kidney, liver, 0.81 y=0.9x+0.7 853 21
bone marrow
IMX vsSP Blood Liver 0.80 y = 0.6x + 3.1 20 20
IMX vsMC Blood Liver 0.92 y = 0.9x + 2.0 20 20
IMX vsELISA Blood Liver 0.96 y = 1.0x + 2.8 25 23
Abbreviations: ELISA = enzyme-linked immunosorbent assay; HPLC = solid phase extraction/HPLC/ELlSA; IMX = IMX analyser (Abbott);
MC = methylene chloride extraction/ELISA; SP = solid phase extraction/ELISA.
of this instrumentation at all transplant centres, and dure are the slow turnaround time (> 72 hours) in-
the difficulty in analysing a large volume of sam- volved and the inability to directly assay whole
ples on a regular basis, limit the use of this tech- blood samples.
nique to pharmacokinetic and metabolism studies
at the present time. 2.5 Comparison of Methods
The absence of any significant correlation be-
tween the concentration of tacrolimus in whole A comparison of different methods of measur-
blood, as measured by HPLC-MS, and in plasma, ing tacrolimus is given in table III.
as measured by ELISA, has been reportedP7 1 Re- A comparison of the SepPak®-ELISA method
cently, a simplified HPLC-MS assay has been re- with the bioassay method for plasma indicates a
ported for measuring tacrolimus in whole blood significant correlation, but consistently higher
and urine samples,l391 In contrast to previous re- estimates of tacrolimus by the ELISA method.
ports, cross-validation of this assay with the MEIA This observation suggests that metabolites of
method showed a significant correlation between tacrolimus cross-react with the antibody used in
the 2 assay methods (r =0.915). ELISA,l2gj Corticosteroid use and poor liver func-
tion appear to magnify the differences between
2.4 Bioassay these 2 assays.l28,401 While the low tacrolimus con-
centration estimates from bioassay were predictive
A biological assay based on inhibition of the of the growth of lymphocytes from liver biopsies,
alloantigen-driven proliferation of a clone of al- SepPak®-ELISA could not discriminate between
loreactive T cells has been reported by Zeevi et those biopsy samples from which lymphocytes can
al.[ 28 1 While this assay provides the tacrolimus be grown and those samples from which they can-
equivalent (any metabolites with activity being not be grown.[41]
measured as tacrolimus) in a biological specimen, The blood concentrations of tacrolimus as mea-
based on a bioassay, the limitations of this proce- sured by MEIA have been reported to correlate
© Adis International limited. All rights reserved. Clin. Pharmacokinet. 29 (6) 1995
well with those of the ELISA method;121,23,34] both 2.6 The Matrix Effect
methods are nonspecific, as they also measure
The whole blood concentrations of tacrolimus
some of the metabolites of tacrolimus. A method
are significantly higher compared with the corre-
which uses HPLC prior to ELISA, MEIA or a mass
sponding plasma concentrations, independent of
spectrometric method is specific for the parent
the method of analysis of tacrolimus. It is also clear
tacrolimus molecule. Other methods seem to mea- that one cannot extrapolate blood concentrations
sure additional tacrolimus-related components in from a measurement of plasma concentrations in
blood or plasma, owing to the nonspecificity of the transplant recipients, due to variable slopes and
monoclonal antibody used. Larger discrepancies poor correlations between the 2 variables. These
between different methods are observed in blood results are summarised in table IV.
samples obtained from patients with impaired liver
function, indicating the accumulation of some me- 3. Pharmacokinetics
tabolites of tacrolimus which cross-react with the
antibody used in the assay procedure. 124 ,25,36 1 Currently, most of the pharmacokinetic data
The blood concentrations of tacrolimus as mea- available for tacrolimus are based on an ELISA
sured by the MEIA method do not correlate well analysis of blood or plasma samples that simulta-
neously measures some of the metabolites of
with plasma concentrations as measured by the
tacrolimus.
SepPak®-EIA method I19 ,34] and, therefore, are not
The pharmacokinetic parameters derived for
interconvertible by using a simple factor.
tacrolimus are a function of the biological fluid an-
Of the 2 assay methods currently used clinically
alysed (significant differences exist between the
to measure the blood concentrations of tacrolimus blood, plasma and serum concentrations of the
(PRO-TRAC® ELISA and MEIA), the ELISA drug), the analytical methods used to measure
method generally tends to have a higher coefficient tacrolimus concentrations (specific or nonspecific)
of variation than the MEIA method, while the and the duration of study (I administration interval
MEl A method lacks the sensitivity required for vs single-dose studies). Pharmacokinetic parame-
routine clinical use. There is a need for the devel- ters such as clearance and volume of distribution
opment of an improved assay procedure that would based on plasma concentrations will be higher than
be of greater clinical use. the clearance and volume of distribution based on
Table IV. Comparison of different methods for measuring tacrolimus (blood vs plasma) concentrations
Methods Transplant Temperature No. of Equation r2 Reference
population separation (C) specimens y = mx+b
SP-WB vs SP-PL Liver 37 58 Y = 4.0x + 3.5 0.52 25
SP-WB vs SP-PL Liver 24 20 Y = 5.7x + 6.9 0.54 20
SP-WB vs SP-PL Kidney 37 43 Y = 11.3x + 7.0 0.50 25
MC-WB vsMC-PL Liver 37 58 y=4.1x+4.7 0.47 25
MC-WB vs MC-PL Kidney 37 37 Y = 12.2x + 7.5 0.31 25
HPLC-WB vs HPLC-PL Liver 37 36 y=7.7x+3.9 0.59 25
HPLC-WB vs HPLC-PL Kidney 37 38 Y = 11.9x + 7.4 0.44 25
MC-WB vs SP-PL Liver 24 20 Y = 3.1x +6.9 0.52 20
MC-PL vs SP-WB Liver 24 20 Y = 0.OO5x + 0.08 0.32 20
MC-PL vs MC-WB Liver 24 20 Y = 0.008x + 0.08 0.38 20
IMX vsSP-PL Liver 24 20 Y = 5.7x + 6.9 0.56 20
IMX vs MC-PL Liver 24 20 Y = 19.5x + 8.9 0.41 20
Abbreviations: ELISA = enzyme-linked immunosorbent assay; HPLC = solid phase exlraction/high-periorance liquid chromatography/ELISA;
MC = methylene chloride exlraction/ELlSA; PL = plasma; SP = solid phase extraction/ELISA; WB = whole blood.
whole blood concentrations, as the concentration 10
of tacrolimus in the blood is higher than the con-

centration of tacrolimus in plasma. On the other :::Ja
hand, pharmacokinetic parameters such as clear- ~c
ance and volume of distribution will be underesti- o
~6
mated when a nonspecific assay method (ELISA, 'E
Q)
()
MEIA) is used in comparison with the parameters c
derived based on a specific assay method (HPLC-
8 4
(1)
E
MEIA, HPLC-MS). '"
Studies involving blood sampling over a dose
£2
interval (normally 12 hours) that is less than or
equal to 1 terminal disposition half-life provide 2 4 6 a 10 12
smaller half-life estimates compared with a single- Time (h)
dose kinetic study, in which blood samples are col-
Fig. 2. Tacrolimus plasma concentration-time profile after a 5mg
lected over multiple half-lives, and the terminal dose given orally to 5 different liver transplant patients. Different
disposition half-life can be more precisely esti- symbols represent different patients.
mated)42] The above information must be borne in
mind when interpreting the available kinetic data
2))42-44,49,51] A lag time of 0 to 2 hours has also
for tacrolimus. The pharmacokinetics of tacro-
limus have previously been summarised by Ven- been reported in some liver transplant recipients.[51]
kataramanan et aI.,[43-45] Peters et aI.,[46] Hooks,[47] Poor aqueous solubility of tacrolimus (and there-
Steinmiiller,[48] Venkataramanan and Warty[49] and fore dissolution rate-limited absorption) and alter-
Kelly et aJ.l50] ations in gut motility in transplant patients may
Tacrolimus is primarily used in transplant pa- account for these observations. The shape of the
tients who receive an organ that is either involved plasma concentration-time profile in some patients
in the absorption (small bowel) or elimination (sharp peaks), and the higher dose-normalised
(liver) of the drug. The physiological status of the maximum blood concentration (Cb,max) at lower
organs transplanted is expected to influence the ab- doses that is seen in some patients who received
sorption (small bowel recipients), distribution (all different doses, are suggestive of the involvement
transplant patients) and metabolism (all transplant of a zero order/saturable process in the absorption
patients) of tacrolimus. Time-dependent changes of tacrolimus[52J (Venkataraman et aI., unpublished
in the absorption, distribution and metabolism of observations). Accordingly, the uptake of tacro-
tacrolimus are also anticipated in patients receiving limus in the rat intestinal ring has been shown to
tacrolimus therapy (time-dependent haematocrit and be a saturable process.[53] These results would then
plasma protein concentration changes altering the
suggest that it may be better to administer the daily
distribution, and time-dependent changes in the ac-
dose of tacrolimus in multiple divided doses to in-
tivity of the liver enzymes responsible for the me-
crease the overall exposure of the patients to the
tabolism of tacrolimus altering the elimination).
drug.
The oral bioavailability of tacrolimus is poor
3.1 Absorption
and ranges from 4 to 89% (mean of around 25%)
Tacrolimus is absorbed rapidly in most patients, in kidney and liver transplant recipients and in pa-
with peak plasma/blood concentrations being tients with renal impairment)42,44,51,54-56] The bio-
reached in about 0.5 to 1 hour, while in others the availability of tacrolimus is similar in small-bowel
drug is absorbed slowly over a prolonged period, transplant recipients with a closed stoma; however,
yielding essentially a flat absorption profile (fig. the bioavailability of tacrolimus is lower in patients
© Adis International Limited. All rights reserved. Clin. PhOrmacokinet. 29 (6) 1995
with open stoma compared with those with closed ity of the solid dispersion of tacrolimus in dogs.l 60]
stoma. L57 ] Unusually high bioavailability (89% and Due to the lack of any effect of bile on the bioavail-
93%) was observed in I small-bowel transplant ability of tacrolimus, overlap of intravenous and
patient on 2 separate occasions. The specific reasons oral tacrolimus therapy is not necessary in liver
are not clear at this time. transplant patients, as is the case with cyclosporin.
The rate of absorption and the bioavailability of This means that tacrolimus has a particular advan-
tacrolimus after oral administration appear to be tage over cyclosporin in liver transplant recipients.
variable in all the patient populations studied, irre-
spective of the organ transplanted. In general, oral 3.2 Distribution and Protein Binding
doses of tacrolimus should be 3 to 4 times higher
than intravenous doses to achieve comparable drug In transplant recipients, the blood tacrolimus
exposure after oral and intravenous administration. concentration is significantly higher (average 15
Based on the low blood clearance of tacrolimus, it times; range 4 to 114 times) than the corresponding
plasma concentrations.[14,17,35,43,51,61,62] This is due
can be predicted that the low bioavailability of
to the extensive binding of tacrolimus to the red
tacrolimus is either due to gut metabolism or to
blood cells [maximum amount bound (Bmax) = 418
poor oral absorption of the drug. Incomplete ab-
± 258 ~glL and apparent dissociation constant (K D)
sorption of tacrolimus is largely responsible for the
low bioavailability of tacrolimus in rats.l 58 ] In-
=3.8 ± 4.7 ~glLin transplant patients; Bmax = 1127
~g/L and KD = 13.5 ~glL in healthy adults]. The
creased availability of tacrolimus from a solution
reasons for the differences between healthy adults
dosage form of tacrolimus in comparison with the
and transplant patients are not clear at this time.
currently available solid dispersion formulation,
The diffusion oftacrolimus from erythrocytes is
also supports this hypothesis (Venkataraman et aI.,
slow in comparison with the transit time of blood
unpublished observations). On the other hand, me-
through an organ, but tacrolimus is readily released
tabolism of tacrolimus by microsomes obtained from the erythrocytes,[63.65] and the binding of tac-
from dog jejunum supports the potential involve- rolimus to erythrocytes may in part protect it from
ment of gut metabolism in reducing the oral bio- hepatic metabolism.l69 ] Tacrolimus does not bind
availability of tacrolimus (Venkataraman et aI., un- to haemoglobin. An intracellular protein in eryth-
published observations). rocytes , with a molecular weight range (14 to
Tacrolimus is bioavailable to a similar extent in 15kD) corresponding to FKBP,[63] or a molecular
paediatric and adult transplant patients[56] (Ven- weight of 11 to 12kD[67] appears to be primarily
kataraman et aI., unpublished observations). Tacro- responsible for binding tacrolimus. As the concen-
limus, however, is poorly bioavailable in patients tration of tacrolimus increases in whole blood, the
awaiting renal transplantation (mean bioavailabil- uptake of tacrolimus by erythrocytes is saturated,
ity of 14 ± 12%; range 6 to 36%).[42] This observa- resulting in a lower blood: plasma ratio.l 17 ,63,65,67]
tion is of importance in oral administration of tacro- In human plasma, most of the tacrolimus is as-
limus during the immediate postoperative period. sociated with the lipoprotein-deficient fraction.
In contrast to what is known about cyclosporin, Unlike cyclosporin, tacrolimus does not signifi-
clamping of the T-tube in liver transplant recipients cantly associate with the lipoprotein fraction in
does not alter the trough concentrations or area un- plasma.l44 ,63,67,68] Nearly 72 to 77% of the drug in
der the plasma concentration-time curve (AUC) of the plasma is bound to plasma proteins, as deter-
tacrolimus.l 44 ,59] This implies that there is no need mined by ultracentrifugation.l 63 ,66] In contrast, a
to change the dose of tacrolimus when the T-tube higher extent of binding (98.8%) of tacrolimus in
is clamped in a liver transplant recipient. Complete human plasma has been reported, based on ultra-
biliary diversion or addition of bile salts appear to filtration studies.l67 ] This observation may in fact
have no significant effect on the oral bioavailabil- reflect an artefact of the methodology (nonspecific
© Adis International Limited. All rights reserved . Clin. Pharmacokinet. 29 (6) 1995
Table V. Characteristics of tacrolimus and its metabolites

Parent drug/metabolite (code name) Molecular ICso Immune- Identified in:
weight" (mg/L) cross-reactivity
Tacrolimus 804 0.11 100
13·G-Demethyl·tacrolimus (MI)b 790 1.71 Nil Liver microsomal system (rat, baboon,
human, rabbit);
blood & urine (human)
15·G-Demethyl·tacrolimus (Mil) 790 >1000d 90.5 Liver microsomal system (rat, baboon,
human);
41lg/mld blood & urine (human)
31-G-Demethyl-tacrolimus (MIII)C 790 0.11 109.0 Liver microsomal system (rat, baboon,
human);
13,15-G-Didemethyl-tacrolimus (MIV) 776 >1000 Nil Liver microsomal system (rat, baboon,
human)
13,31-G-Didemethyl-tacrolimus (MV) 776 8.78 Nil Liver microsomal system (rat, baboon);
15,31-G-didemethyl-tacrolimus (MVI) 776 >1000d 92.2 Liver microsomal system (rat, baboon);
325d blood & urine (human)
Metabolite of tacrolimus with a 821 15.27 Nil Liver microsomal system (rat)
10-membered ring (MVII)
14-Hydroxy-tacrolimus (MVIII) 820 3.13 8.8 Liver microsomal system (rat, baboon);
bile (human)
Epoxide of tacrolimus (MIX) 820 Plasma (human)
Dihydroxydiol of tacrolimus (MX) 838 Liver microsomal system (baboon);
plasma (human)
Dihydroxylated tacrolimus (MXI) 836 Plasma (human)
Dihydroxydiol of tacrolimus with a 854 Plasma (human)
7-membered ether ring (MXII)
Tetrol of tacrolimus (MXIII) 872 Plasma (human)
Tri-demethylated, hydroxylated 794 Liver microsomal system (rabbit)
tacrolimus epoxide (MXIV)
Di-demethylated, hydroxylated 792 Liver microsomal system (baboon);
tacrolimus (MXV) bile (human)
Phase II metabolites' Bile (rat, human)
a From mass spectrometry, mass/charge (MIZ).
b Major metabolite.
c Active metabolite.
d Different results were reported, perhaps related to differences in solubility of metabolites.
e Venkataraman et aI., unpublished observations.
adsorption onto the devices) used. Equilibrium The partitioning of tacrolimus between erythro-
dialysis and ultrafiltration are not suitable for cytes and plasma is dependent on the concentration
evaluating the protein binding of tacrolimus be- of tacrolimus, haematocrit, sample temperature
cause of adsorption of tacrolimus onto the mem- and concentration of plasma proteins responsible
branesJ63] for tacrolimus bindingJ35,62,63,65,67 1 Alterations in
The plasma protein binding of tacrolimus is not these variables will influence the relative distribu-
saturated up to 50 Ilg/L, but is saturable at higher tion of tacrolimus between blood cells and plasma.
concentrations. Tacrolimus is primarily associ- It is well known that haematocrit increases with
ated with ai-acid glycoprotein (AAG), an acute- time after transplantation in renal transplant recip-
phase protein. I16.63.671 and albumin.[661 ients. This will tend to increase the blood: plasma
ratio of tacrolimus in these patients. 162 ,63,67] At sam- sible for the binding of tacrolimus in lymphocytes.
ple temperatures of up to 25°C, there is no differ- It has been reported that the actual concentration of
ence in the distribution of tacrolimus within the tacrolimus per cell is greater in lymphocytes than
blood. However, at higher temperatures, relatively in red blood cells. 167 ]
more drug stays in the plasma compart- Tacrolimus accumulates in high concentrations
ment. 162 ,63,67] The concentration of AAG in plasma in organs such as lungs, spleen, heart, kidney, pan-
creas, brain, muscle and liver, in comparison with
is also known to increase with time after transplan-
blood or plasma, of rats and monkeys.l72,73] So far,
tation. An increase in AAG concentration leads to
the presence of tacrolimus in cerebrospinal fluid
a significant increase in binding of tacrolimus in has not been documented, even in patients with
plasma. This tends to decrease the blood: plasma tacrolimus-induced neurotoxicity (Venkataraman
ratio of tacrolimus. 163 ] Cyclosporin does not have et aI., unpublished observations). Tacrolimus ap-
any effect on protein binding of tacrolimus. pears to pass through the placenta and reach the
The uptake oftacrolimus by lymphocytes is also fetal circulation. The concentration of tacrolimus
saturable.(70,71] A cytosolic protein with a molecu- in umbilical cord plasma is about 350/0 of the cor-
lar weight range of 18 to 19kD appears to be respon- responding maternal tacrolimus plasma con centra-
tion;l74] hyperkalaemia has been observed in some
Table VI. Involvement of cytochrome P450 (CYP) in tacrolimus neonates, and renal impairment was reported in 1
metabolism baby immediately after birth, but this resolved with
A. Involvement of CYP3A
time. 174 ] The placenta tends to accumulate tacro-
1. Significant correlation between tacrolimus metabolism limus as demonstrated by the fact that placental
and nifedipine oxidation in human liver microsomesl811 concentrations are 4 times greater than maternal
2. Significant correlation between CYP3A4 activity plasma concentrations. The concentration of tacro-
(testosterone 6-~-hydroxylation) and tacrolimus
metabolism l871 limus in breast milk is similar to the plasma con-
3. Metabolism of tacrolimus by reconstituted human centration. Even though the baby is expected to be
CYP3A4181.871 exposed to a very low dose of tacrolimus, breast-
4. Inhibition of tacrolimus metabolism by anti-CYP3A4 feeding is currently not recommended in patients
antibodiesl81 .831
who are on tacrolimus therapy.
5. Inhibition of tacrolimus metabolism by troleondomycin,
gestodene and several CYP3A substratesI81.87.93.941
6. Induction of tacrolimus metabolism by
dexamethasoneI81 .89.931 3.3 Metabolism
7. Lack of induction of tacrolimus metabolism by
phenobarbital and 3-methyl cholanthrenel931
Tacrolimus is primarily eliminated from the
B. Involvement of additional subsets of CYP in the body as several metabolites. Although the liver is
metabolism of tacrolimus
1. Only partial inhibition of tacrolimus metabolism by the primary site of metabolism, there is direct and
anti-CYP3A antibodies l831 indirect evidence for the involvement of the gut in
2. Inhibition of tacrolimus metabolism by anti-CYP1A tacrolimus metabolism I37 ,60] (Venkataraman et aI.,
antibodyl831
unpublished observations). Tacrolimus metabo-
3. Inhibition of tacrolimus metabolism by
7,8-benzoflavoneI831 lites have been isolated from human plasma and
4. Significant correlation between tacrolimus metabolism bile, rat bile, and liver microsomes obtained from
and chlorzoxazone hydroxylation (CYP2E1) and humans, rats, rabbits and baboons,127,37,38,75-90]
7-ethoxycoumarin demethylation (CYP2A6) in vitrd811
(table V). While human and baboon livers are
5. Inhibition of tacrolimus metabolism by quinidine, a
specific inhibitor of CYP2D6 and debrisoquine, a
highly efficient in metabolising tacrolimus, other
substrate for CYP2D6187.941 species metabolise tacrolimus at a slower rate.l 91 ]
6. Metabolism of tacrolimus in untreated female rats Tacrolimus is converted to at least 15 metabolites
showing no classical CYP3A activityl891
(fig. 3).
6> ;;?
r'>
~
<O-
13,15-DemethyHacrolimUS I Demethylallon I 13-Demethyl-tacrollmus a
S"
iii 15,31-Demethyl-tacrolimus Molecular weight" n6 .. 15-Demethyl-tacrolimus Molecular weight" 790 §"
15,31-Demethyl-tacrolimus CYP4503A4? 31- Demethyl-tacrol imus c
V>
~
o:J (J
Q. [
31-Demethyl-tacrolimus; r'>
~ Molecular weight = 790 e:.
~ '"0
0. ::T
~ 14-Hydroxylated tacrolimus '"
,6- c: Molecular weight" 820
9
:J" Metabolite of tacrolimus "".... r'>
or with 10-membered ring 2
<ii .!!!
'"o
~
~ Molecular weight = 821
~ € .. ~.
~
0. ~ r'>
(J V>
~
MFO MFO Epoxide of tacrollmus Hydrase ~ Dihydrodiol of tacrolimus
Molecular weight" 820 Molecular weight = 838
'0
~
3\\Ofl
C'o~£<
Gofl\',}g
9 :9~~o"
.s ~
tl
jg
~
~
~
~ Conjugation Dihydrodiol 01 tacrolimus
_j Conjugates in bile or urine I" I with 8-membered ether ring
~ 1 1 Molecular weight = 854
.§
~
Q
~:r
g Dihydroxylated tacrolimus
with 7-membered ether ring
J f
Molecular weight" 836
~ Hydroxylated tacrolimus Hydroxylated tacrollmus
~ Molecular weight" 820 Molecular weight" 820
':(5
e
~ Fig_ 3_ Metabolic pathway of tacrolimus. Abbreviations and symbols: CYP cytochrome P450; IMR intramolecular rearrangement; MFO mixed function oxidase. ....
"'<.n"
12
11
::11
o Intravenous administration
~c
• Oral administration
9
o
.~ 8
C
g7
8(/) 6
:::l
s:
"2
5
u
~ 4
'~" 3
a::'"
2
O~-r-r---r---.---.---.---.---'---'---'---'---'---'----
o2 4 6 8 10 12 14 16 18 20 22 24 26
Time (h)
Fig. 4. Tacrolimus plasma concentration-time profile (logarithmic scale for concentration) after IV administration (4.5 mg/day, 4-hour
infusion) and oral administration (18 mg/day) in a liver transplant patient.
The involvement of cytochrome P450 in the me- tacrolimus) and demethylhydroxy metabolites (ap-
tabolism of tacrolimus was confirmed by measur- proximately 10% of the AUC of tacrolimus) being
ing the formation of adrenochrome, which indi- the major metabolites.l 96 ] In urine, demethyl-
cates the formation of oxygen radicals.1921 There is tacrolimus was the primary metabolite. The immu-
strong evidence to suggest that cytochrome P450 nosuppressive activity of 31-0-demethyl-tacrolimus
(CYP) 3A4 is involved in the metabolism of was comparable to that of tacrolimus, but this me-
tacrolimus.l 81 ,83,93 1 The evidence for this, and for tabolite has not been reported in the human blood
the involvement of other isoenzymes in the meta- so far. 13-0-Demethyl-tacrolimus has been ob-
bolism of tacrolimus, is summarised in table VI. served in blood, and is approximately one-tenth as
Hydroxylation and demethylation appear to be the active as tacrolimus in a mixed mouse lymphocyte
major metabolic pathways involved (see fig. 3), reaction, while the other metabolites had little or no
13-0-Demethyl-tacrolimus appears to be the activity,185,86] The immuno-cross-reactivity of 31-
major metabolite of tacrolimus in human liver O-demethyl-tacrolimus, 15-0-demethyl-tacrolimus
microsomesl 83 ] and in patient blood. 127 ,751 Five me- and 15.31-0-didemethyl-tacrolimus with the
tabolites (a dihydrodiol, a dihydrodiol with a 7- mouse anti-tacrolimus monoclonal antibody used
membered ring ether structure, a dihydrodiol with in the ELISA assay were comparable to that with
tacrolimus,186] More studies are needed to evaluate
an 8-membered ether ring structure, a tetrol and a
the potential contribution of the metabolites of
dihydroxy derivative of tacrolimus) have been
tacrolimus to the immunological and toxic effects
identified in human plasma,f76] Five metabolites
observed after tacrolimus therapy,
(demethyl-, demethylhydroxy-, didemethyl-, di-
demethylhydroxy-, and hydroxy-tacrolimus) have
3,4 Excretion
been reported in blood samples obtained from liver
transplant and renal transplant recipients,[95] with Less than I % of the intravenous dose of tacro-
the demethyl (approximately 3% of the AUC of limus is excreted in the urine of liver transplant
© Adis International Limited. All rights reserved. elin. Pharmacokinet. 29 (6) 1995
recipients as unchanged tacrolimus as determined 25
by the ELISA method. Renal clearance of tacro- ::J • Blood

0,
.320 • Plasma
limus is less than I % of total body clearance.[441 A c
0
small amount of tacrolimus conjugate also appears
in the urine.[821 Less than 1% of unchanged tacro-
~c 15
Q)
limus, or tacrolimus metabolites which cross-react "c

810
with the monoclonal antibody used in the ELISA rJ)
:::l
assay, is excreted in the bile. Small amounts of the .S:

e 5
conjugates of tacrolimus or its metabolites appear "'"
I-
in the bile. Animal studies using radioactive tacro- 0
limus indicate that biliary excretion is the major 0 5 10 15 20 25
Time (h)
pathway of excretion of tacrolimus metabolites. 1581
Fig. 6. Tacrolimus plasma and whole blood concentration-time
profile after continuous IV infusion (0.15 mg/kg/day) in a liver
3.5 Pharmacokinetic Parameters transplant recipient.
The plasma and blood concentration-time pro-

The mean terminal disposition half-life of
file of tacrolimus after a short infusion (4 hours)
tacrolimus has been reported to be 8.7 hours,[72]
are shown in figures 4 and 5. Figure 6 illustrates 11.3 hours,[43- 45 1 12.1 hours,[51] 26 hours,[96] 32
the blood and plasma concentrations of tacrolimus
hours 1103 ] and 32.5 hours.[42] Typically, short half-
after continuous intravenous infusion in a liver
lives have been reported in studies carried out in
transplant recipient. A 2-compartment model
patients during 1 administration interval (normally
seems to adequately describe the concentration-
12 hours), while long half-lives have been reported
time profile.l42.971 A I-compartment model with
in transplant recipients, nontransplant patients and
nonlinear binding to red blood cells has also been
used to describe the tacrolimus plasma concentra- in healthy people who received a single dose
tion-time profile after intravenous infusion. [51] and/or who were studied for 72 hours after a dose.
The lower half-life estimate obtained in transplant
The various pharmacokinetic parameters of
recipients, however, is consistent with the observa-
tacrolimus are summarised in tables VII and VIII.
tion that near-steady-state blood concentrations
are reached in most patients within 36 to 48 hours
2
• Oral of administration of tacrolimus .
• Intravenous
Tacrolimus was originally considered to be a
high-clearance drug (plasma clearance greater than
102 Llh, exceeding the blood flow to the liver),
based on plasma concentration measurements and
in the absence of any data on blood: plasma ratios.
With the availability of assays for measuring
tacrolimus in whole blood, it is clear that tacro-
limus is in fact a low-clearance drug (blood clear-
ance of about 6 Llh). In liver transplant recipients,
0;-----,----.-----.----.-----.----,
o 2 4 6 8 10 12 there was an apparent correlation (r = 0.76) be-
Time (h) tween the plasma clearance and the blood: plasma
ratio of tacrolimus because of the strong binding
Fig. 5. Blood concentrations (logarithmic scale) of tacrolimus in
a liver transplant recipient after oral administration on day 1 and of tacrolimus to erythrocytes and its slow efflux
after a short intravenous infusion on the following day. into plasma.l 511 The binding of tacrolimus to eryth-
Table VII. Pharmacokinetics of tacrolimus (determined using enzyme-multiplied immunoassay)

Patient population No. of Biological Dose (mglkg) t,;"z Vss CL F(%) tmax Reference
pts fluid [route] (h) (Ukg) (Uh) (h)
Liver transplant 9 Plasma 0.15 [IV] 15.5 ± 11.2 17.9±9.8 105.6 ± 105.0 59
Liver transplant 3 Plasma 0.15 [IV] 3.5-40.5 5-56 25.2-366 27 1-4 72
Liver transplant 5 Plasma 0.15 [IV] 6.9-11.5 53.3-243.6 98
Liver transplant 9 Plasma 0.15 [IV] 4.5-33.1 5.8 ± 34.9 21.6-345 99
Liver transplant 16 Plasma 2.7-21.6mg [IV] 12.1 ±4.7 30.1 ± 14.7 118.3±39.9 25± 10 51
16 Blood 4-12mg[PO] 12.1 ±4.7 0.906±0.29 3.8± 1.2 25± 10 51
Hepatic dysfunction 5 Plasma 0.15 [IV/PO] 38.5 195 36 0.5-2 59
High dose 17 Plasma 0.4-1.3 [PO] 145.7±82.3 15 33
Small bowel
transplant:
open stoma 2 Plasma 0.15 [IV/PO] 53.2 - 222.6 5-10 2.8 57
closed stoma 3 Plasma 0.15 [IV/PO] 43 2.8
Kidney transplant 12 Blood 0.02 [IV] 22±6.7 0.9 ± 0.21 2.8±0.9 12.1 ±4.2 54
0.08 [PO]
Kidney transplant 15 Blood 0.02 [IV] 17.6 1.58 ± 0.45 6.8 ± 3.5 22.4 ± 14.2 100
Awaiting kidney 6 Blood 0.02 [IV/PO] 32.5 ±8.3 1.24 ±0.26 2.4 ± 1.1 14.1 ± 12.4 1.4 ± 42
transplant 0.6
Kidney transplant 7 Blood 0.02 [IV] 1.5 ± 0.27 21 ± 19 101
Kidney transplant 37 Plasma 0.15 [IV] 6.86 ± 2.9 2.5± 102
0.3 [PO] 2.4
Kidney transplant 37 Blood 0.15 [IV] 8.04 ±4.87 2.4 ± 102
1.9
Healthy individuals 5 Plasma 43± 15 17±7 34± 11
Healthy individuals 5 Blood 32± 10 0.87 ±0.22 2 ± 0.45 15.9 48
Abbreviations and symbols: Cmax = maximum plasma concentration; CL = total systemic clearance from the plasma; F = bioavailability;
IV = intravenous; PO = oral; t,;"z = terminal elimination half-life; tmax = time to Cmax; Vss = volume of distribution at steady-state.
rocytes is expected to limit its clearance, and ap- centration ratio, indicating the red blood cell bind-
pears to be a major factor accounting for the large ing to be a major factor in the interindividual dif-
interpatient variability in the pharmacokinetics of ferences in the volume of distribution of tacro-
tacrolimus. Nonlinear erythrocyte binding and limus.l 511
slow efflux of tacrolimus from erythrocytes com-
plicate the pharmacokinetic interpretation of
plasma concentration-time profiles for tacrolimus. 4. Factors Affecting Tacrolimus
The volume of distribution (V p) of tacrolimus Pharmacokinetics
based on the plasma concentration measurement
is greater than 20 Llkg197,S1 I indicating extensive Some of the factors affecting the absorption and
distribution of tacrolimus outside the plasma com- distribution of tacrolimus have been discussed in
partment. The extensive binding of tacrolimus into sections 3. 1 and 3.2.
red blood cells, however, leads to a lower estimate Paediatric patients require higher doses of tacro-
of the volume of distribution (Vb) [approximately Iimus on a mg/kg basis, compared with adults.l 99,I051
I Llkg) based on blood tacrolimus concentrations. This appears to be a result of the higher clearance
There is a strong linear relationship (r = 0 .73) of tacrolimus in children l561 (Venkataraman et aI.,
between Vp and the maximum blood: plasma con- unpublished observations). The bioavailability of
centration ratio, and a poor relationship (r = 0.3) tacrolimus in children appears to be similar to that
between Vb and the maximum blood: plasma con- observed in adults.
© Adis International Limited. All rights reserved. Clin. Pharmac okinet. 29 (6) 1995
Tacrolimus concentrations were elevated in pa- Table VIII. Summary pharmacokinetics of tacrolimus
tients with poor liver function compared with patients Parameter Range Mean
with near-normal liver function.[34.59] Tacrolimus Absorption
has a longer disposition half-life and reduced clear- Absorption rate constant. ka (h- 1) 0.14-8.0 4.5
ance in patients with liver impairment compared Time to Cmax• tmax (h) 0.5-6.0 2
with patients with normal hepatic functionJ59.97] Cmax at steady-state. Cssmax 0.1-0.8
(~g/Umg dose)
This is consistent with the fact that tacrolimus is Bioavailability, F (%) 4.0-93 25
primarily metabolised before elimination from the
Distribution
body. The elevated concentrations of tacrolimus in Blood/plasma ratio in transplant 4-114 15
patients with impaired liver function are associated patients
with significant nephrotoxicity)124.125] Elevated Percentage bound in normal plasma 77
concentrations of tacrolimus metabolites have Percentage bound to human albumin 69
(4 g/dl)
been reported in patients with liver dysfunction,
Percentage bound to human cx1-acid
indicating impaired biliary secretion of these me- glycoprotein:
tabolites.[27] As expected, there was no significant 83 mg/dl 67
correlation between serum creatinine levels and 160 mg/dl 91
clearance of tacrolimus (r = 0.36).[42] Percentage associated with 24
lipoprotein
Most patients achieve therapeutic tacrolimus Volume of distribution, V (Ukg):
concentrations with a dosage of 0.3 mg/kg/day or plasma 5.0-65 30
less. However, there is a small percentage of pa- blood 0.5-1.4
tients (3%) who require> 0.4 mg/kg/day to achieve Elimination
this)33] This is predominantly the result of low bio- Percentage metabolised >99
availability of tacrolimus and, to a minor extent, of Urinary excretion of unchanged drug <1
the high clearance of tacrolimus. Poor bioavaila- (%)
bility is observed in a greater percentage of non- Terminal disposition half-life (h) 4.0-41 12
Total body clearance. CL:
Caucasians (Asians, Blacks, Hispanics) when
blood (Uh/kg) 0.03-0.09 0.06
compared with Caucasians, suggesting possible plasma (Uh/kg) 0.6-5.4 1.8
racial differences in tacrolimus pharmacokinetics
(Venkataraman et aI., unpublished observations).
lished observations). Separation of the administra-
5. Drug Interactions tion of these 2 agents by at least 2 hours, or the
replacement of sodium bicarbonate by sodium ci-
Transplant recipients generally receive multiple trate and citric acid, results in stable trough plasma
drug therapy, which predisposes them to a number tacrolimus concentrations in patients. It is recom-
of potential drug-drug interactions (table IX).
mended that magnesium oxide, sodium bicarbon-
Aluminium hydroxide gel appears to physically
ate and aluminium hydroxide gel be administered
adsorb tacrolimus in vitro)106] Other in vitro stud-
to patients at least 2 hours apart from tacrolimus.
ies indicate that tacrolimus concentrations are
Magnesium chloride, aluminium hydroxide pow-
significantly decreased in the presence of magne-
sium oxide[106] due to a pH-mediated degradation. der, aluminium hydroxide dried gel or calcium car-
Widely variable trough plasma tacrolimus concen- bonate do not appear to alter tacrolimus concentra-
trations were observed in patients taking sodium tions in simulated gastric fIuid.l 106]
bicarbonate temporally close to tacrolimus ad- Coadministration of a low-fat diet appears to
ministration. Coadministration of tacrolimus with have minimal or no effect on the extent of tacro-
sodium bicarbonate results in lower blood concen- limus bioavailability, but delays the time to reach
trations oftacrolimus (Venkataraman et aI., unpub- maximum concentrations of tacrolimus[107] (Ven-
Table IX. Drug-drug interactions involving tacrolimus and other drugs

Drug Observation
Agents that decrease tacrolimus concentrations

Aluminium hydroxide In vitro adsorbs tacrolimus (40% loss immediately)
Magnesium oxide In vitro pH mediated degradation (complete loss in 1 hour)
Sodium bicarbonate In vitro pH mediated degradation (75% loss in 24 hours), in patients with decreased
bioavailability (>50%)
Rifampicin (rifampin) Induction of metabolism (50% decrease in trough plasma concentration in patients; >50%
reduction in blood concentrations in rats)
Dexamethasone Induction of metabolism (>3-fold increase in metabolism in rats)
Agents that increase tacrolimus concentrations

Ery1hromycin Inhibition of metabolism (>4-fold increase in trough plasma concentrations in patients; 3- to
4-fold increase in blood concentrations in rats)
Clotrimazole Inhibition of metabolism (2- to 3-fold increase in trough plasma concentration in patients)
Fluconazole Inhibition of metabolism (2- to 3-fold increase in trough plasma concentration in patients; 10-fold
increase in blood concentration in rats)
Danazol Inhibition of metabolism (>5-fold increase in trough plasma concentration in patients; 3-fold
increase in blood concentrations in rats)
Itraconazole Inhibition of metabolism (2-fold increase in trough plasma concentrations in patients; 2-fold
Chloramphenicol Inhibition of metabolism (3- to 4-fold increase in trough plasma concentrations in patients)
Ketoconazole Inhibition of metabolism (2-fold increase in trough plasma concentrations in patients; 2-fold
Diltiazem Inhibition of metabolism (4-fold increase in blood concentrations in rats)
Verapamil Inhibition of metabolism (2-fold increase in blood concentrations in rats)
Cimetidine Inhibition of metabolism (3-fold increase in blood concentrations in rats)
kataraman et aI., unpublished observations). A meal danazol, verapamil and cimetidine increase blood
with moderate fat content significantly reduces tacrolimus concentrations. [I 12] The metabolism of
the rate and extent of tacrolimus bioavailability tacrolimus in vitro by dexamethasone-induced rat
(by approximately 30%) in transplant recipients.[IDO] liver microsomes is inhibited by ketoconazole,
It is important to be consistent in taking tacrolimus itraconazole, fluconazole, SKF525A, debrisoqu-
in relation to food intake. The effect of coadminis- ine, quinidine, norethindrone, erythromycin, lido-
tration of tacrolimus with grapefruit juice, a com- caine (lignocaine), danazol, veraparnil, nicardipine,
ponent of which is known to inhibit intestinal nifedipine, diltiazem, midazolam, mephenytoin and
CYP3A enzymes, is not presently known. dapsone.[94] Metabolism of tacrolimus in vitro by
Since tacrolimus appears to be metabolised pri- human liver microsomes is significantly inhibited
marily by CYP3A4, an enzyme known to metabo- (>20%) by diltiazem, erythromycin, fluconazole,
lise cyclosporin, it is anticipated that drugs known nifedipine, nilvadipine, prednisolone, rifampicin
to affect blood cyclosporin concentrations are (rifampin), cyclosporin, ethinylestradiol, ampho-
also likely to affect tacrolimus blood concentra- tericin B, and mildly inhibited «20%) by enoxacin,
tions in patients (table VIII). Administration of lincomycin, ofloxacin and norethindrone)84] In
erythromycinJ 108] ciotrimazole,l'09] fluconazole,[J 10] rats, tacrolimus blood concentration is not signifi-
danazol [I I II and chloramphenicol (Venkataraman cantly affected by carbamazepine, phenobarbital
et aI., unpublished observations) appear to increase (phenobarbitone) and phenytoin pretreatment, but
the plasma or blood concentration of tacrolimus in is decreased by rifampicin and dexamethasone pre-
transplant recipients. In rats, erythromycin, keto- treatment (Venkataraman et aI., unpublished obser-
conazole, fluconazole, itraconazole, diltiazem, vations). While the use of abovementioned drugs
with tacrolimus is not contra-indicated, it is impor- to be of some benefit in treating patients who take
tant to monitor tacrolimus blood concentrations an oral overdose of tacrolimus.
while using agents that are known or expected to Tacrolimus is highly bound to red blood cells
affect tacrolimus pharmacokinetics, so that alter- and plasma proteins (see section 3.2), and is not
ations in tacrolimus dosage can be made, in order readily dialysable, so haemodialysis will be oflim-
to minimise toxicity or to prevent graft rejection. ited use in treating tacrolimus overdose. In 2 pa-
Combined use of tacrolimus and cyclosporin re- tients, it was possible to reduce tacrolimus concen-
sults in synergistic immunosuppression and in- trations in plasma by continuous ultrafiltration,l l23 1
creased nephrotoxicity. In dogs, tacrolimus kinetics which was possibly the result of physical adsorp-
are not altered by coadministration of cyclosporin tion of tacrolimus onto the device rather than actual
(Venkataraman et aI., unpublished observations). filtration and removal of the drug. The potential
Short term administration of tacrolimus does not benefit of continuous ultrafiltration in treating pa-
affect the systemic clearance of cyclosporin in hu- tients with tacrolimus overdose needs to be further
mans,ll131 but studies in dogs suggest that tacrolimus evaluated. In I liver transplant recipient, it was
increases cyclosporin bioavailability without alter- possible to increase tacrolimus elimination by ad-
ing its systemic clearance. [I 141 This is indicative of ministration of rifampicin; however, this observa-
the possible inhibition of intestinal metabolism of tion requires confirmation in further studies.
cyclosporin by tacrolimus, similar to the mecha-
nism that is reportedly responsible for the erythro- 7. Therapeutic Monitoring of Tacrolimus
mycin-cyclosporin interaction. Tacrolimus is
known to inhibit in vitro hepatic metabolism of
cyclosporin and other drugs at concentrations well 7.1 Rationale for Monitoring
above those observed in patients,l1l5-121]
It is unlikely that, at blood concentrations ob- Tacrolimus is a drug with a narrow therapeutic
served in transplant recipients, tacrolimus will sig- index. Although lower blood concentrations may
nificantly alter the hepatic drug-metabolising ca- precipitate a rejection episode, higher concentra-
pacity of a patient. The effect of tacrolimus on tions may lead to nephrotoxicity and/or neurotox-
prednisolone kinetics is not known, but a possible icity.
inhibition of prednisolone metabolism may ex- There appears to be some relationship between
plain the use of lower doses of corticosteroids in tacrolimus concentration and toxicity in transplant
patients receiving tacrolimus therapy. It is interest- patients. It has been shown that in patients in whom
ing to note that, while long term intramuscular the perioperative graft dysfunction did not im-
administration of tacrolimus increased the pento- prove rapidly, plasma tacrolimus concentrations
barbital-induced sleeping time in rats,l122110w oral were significantly elevated; these patients had a
doses of tacrolimus did not alter the pentobarbital- higher rate of renal dysfunction, often requiring
induced sleeping time. Tacrolimus also has a min- dialysis,l124,125,146] An analysis of the adverse ef-
imal effect on the biliary excretion of bromo- fects of tacrolimus indicated that early onset of
sulphthalein, consistent with a lack of hepatotoxicity nephrotoxicity in several patients, when other neph-
in patients receiving tacrolimus therapy. rotoxic factors were excluded, was significantly as-
sociated with higher tacrolimus plasma concentra-
6. Treatment of Drug Toxicity/Overdose tions (mean value 4.3 flglL) in comparison with
those who did not exhibit any nephrotoxicity
In vitro studies indicate that activated charcoal (mean value 2.3 flglL),l126 1 In 3 additional studies
can completely adsorb tacrolimus from a solution in liver transplant patients, elevated plasmalblood
(Venkataraman et aI., unpublished observations). tacrolimus concentrations were associated with
Thus, administration of activated charcoal is likely nephrotoxicity.l56,127-129]
It is believed that blood/plasma concentration at the time of rejection with a group of patients who
measurement might help to minimise the incidence did not experience any rejection episodes indicated
and severity of tacrolimus-related neurotoxicity no significant differences. It is also interesting to
and nephrotoxicity.l129-13l) In patients with hyper- note that early cellular rejection after liver trans-
bilirubinaemia, plasma concentrations enabled dif- plantation correlated better with low concentra-
ferentiation between toxicity and rejection;(20) the tions of tacrolimus in hepatic tissue and not with
trough blood concentration of tacrolimus has been plasma concentrations.l l34 )
reported to be significantly higher in patients with A number of variables, such as the lise of other
renal impairment than in those with acute rejection. nephrotoxic drugs, use of other immunosuppres-
A clear relationship between other adverse effects sive drugs, potential differences in the binding of
of tacrolimus (hypertension, hyperkalaemia, glu- tacrolimus to blood proteins, clinical status of the
cose intolerance) and drug concentrations has not patients and the immune sensitivity of a patient
yet been demonstrated. (extent of mismatch), may well contribute to the
In the case of immunosuppressive drugs such as overall differences in the immunosuppression and
cyclosporin and tacrolimus, it is difficult to estab- toxic symptoms observed in patients.
lish a concentration-response (graft failure) rela- The pharmacokinetics of tacrolimus are highly
tionship, in view of the grave consequences of a variable between patients (fig. 2) and within indi-
lack of response (rejection) to the drug, the lack of a vidual patients over a period of time.!33,44-45,49,51,133]
good specific response parameter that can be mon- This is reflected in the wide range of oral dosages
itored, and because of the practice of using combi- of tacrolimus (I to 44 mg/day) that are required to
nation therapy with other immunosuppressive maintain trough plasma concentrations of 0.5 to
agents (such as corticosteroids and azathioprine). 5 J.lglL (or to maintain trough blood concentrations
A comparison of tacrolimus plasma concentra- of 5 to 20 J.lglL) in clinically stable liver and kidney
tions! 132.133) or blood concentrations! 133) in patients transplant patients (fig. 7). Patients who were
5.0 •
•
4.5 • •
•
• • •
4.0
• • • •
~ 3.5 • •• • •• •
•
3 • • •
• •
§ 3.0 • •• •• •
e
c • • •• • •
2l 2.5 • •• • • • •
• • • • • ••• •
c
0
~
• • •
2.0
•• • • •• ••
E
••• •• • •
a::'"'" 1.5 • • •••••• •••• •• ••• • •• •• • • •
•
•• • • •• •• • •• • • •
1.0 •• ••• • • ••=• I• •• •• •• ••• •• • ••
•• •• • •• •• • ••• ••
•
• •
0.5 • ••••
• •• •• • • ••
•• ••
0.0
0 5 10 15 20 25 30 35 40 45
Dose (mg/day)
Fig. 7. Dose of tacrolimus on the day of discharge vs plasma concentrations in 620 clinically stable kidney and liver transplant patients.
© Adis Internotionoilimited. All rights reserved. elin. Pharmocokinet. 29 (6) 1995

o Blood concentration of tacrolimus 48

A Plasma concentration of tacrolimus
:J'
• Total bilirubin
40 ~
(J)
:::l
32 eE
g
24 '0c
o
~
16 55
u
c
o
u
8 "8
o
1ii
4 7 10 13 16 19 22
Days post-transplant
Fig. 8. Tacrolimus plasma concentration as measured by enzyme-linked immunosorbent assay (ELISA). blood concentration as
measured by microparticulate enzyme immunoassay (MEIA) and total bilirubin in a liver transplant recipient over time.
maintained on a fixed dose of tacrolimus also ex- concentration is a good indicator of the total body
hibited up to 60% variation in trough plasma con- exposure of tacrolimus.
centrations and up to 50% variation in trough blood
concentrations. [I33J Therapeutic monitoring of tac- 7.3 Methods/Matrix for Monitoring
rolimus will help to optimise tacrolimus therapy in Tacrolimus
these patient populations. Figure 8 is an illustration
Therapeutic monitoring of tacrolimus has been
of blood (MEIA) and plasma (ELISA) concentra-
discussed in several reviews.£3 2,49,I07,136] Tacro-
tions of tacrolimus and bilirubin concentrations in
limus concentrations can be measured in plasma
a liver transplant patient over time.
and blood, although from a clinical perspective it
Monitoring blood/plasma tacrolimus concen-
is not clear at this time whether blood or plasma is
trations helps to ensure patient compliance with
better for measurement of tacrolimus concentra-
drug therapy. This is important, as transplant pa-
tions. However, a recent consensus conference on
tients receive several drugs in the long term and
therapeutic monitoring of immunosuppressive
may tend to become noncompliant with time.
drugs has recommended the use of blood as the
Tacrolimus monitoring may aid in differential di-
matrix for monitoring the concentration of tacro-
agnosis of graft rejection and organ toxicity, and
limus[I04] for the following reasons:
minimise or avoid the consequences of drug inter-
(i) blood concentrations are higher and tend to
actions.
yield a lower coefficient of variation in the analyt-
7.2 Trough Concentration Monitoring ical methodology used compared with plasma sam-
ple measurements;
In liver, small-bowel and kidney transplant re- (ii) the red blood cell uptake of tacrolimus is
cipients, the trough plasma and blood concentra- saturable and temperature-dependent, and necessi-
tions of tacrolimus (measured 12 hours after an oral tates plasma separation at 37°C;
dose) and the AVC values for plasma and blood are (iii) processing of blood samples to obtain
highly correlated (r2 = 0.94 and 0.92, respec- plasma is laborious and time-consuming;
tively;[135] r2 = 0.94 and 0.89, respectively[51] This (iv) haemolysis will artefactually increase
indicates that trough plasma or blood tacrolimus plasma tacrolimus concentrations;
© Adis International Limited. All rights reserved. elin. Pharmacokinet. 29 (6) 1995
424 Venkataramanan et a/.
(v) availability of blood tacrolimus assays; in liver function, presence of adverse effects, use
(vi) in a group of clinically stable patients re- of drugs that may alter tacrolimus kinetics) may
ceiving a fixed dose of tacrolimus, the trough warrant more frequent monitoring.l I04 ]
plasma concentrations appear to be more variable
than the corresponding trough blood concentra- 7.5 Precautions
tions;11331 and
Tacrolimus tends to adsorb onto polyurethane
(vii) there is apparently a better correlation be- and other plastic catheters.fs.138.139] Blood sam-
tween rejection episodes and adverse effects versus
pling via catheters through which tacrolimus is in-
trough blood tacrolimus concentrations than with
fused will artificially elevate tacrolimus concentra-
trough plasma tacrolimus concentrations. tions, and this practice must be avoided at all costs.
Tacrolimus concentration in plasma appears to Capillary blood samples obtained from finger
be independent of the anticoagulant used for ob- pricking give essentially the same results as the
taining the blood samples (Venkataraman et aI., un- venous or the arterial blood sample, and can be
published observations). While ethylenediamine used in patients with limited venous access.11391 As
tetraacetic acid (EDTA) is the preferred anticoagu- tacrolimus is stable in blood, samples can be
lant, its use must be avoided if bioassay is contem- shipped at ambient temperatures for analysis.
plated. Plasma can easily be frozen and repeatedly
measured without loss of tacrolimus for several 8. Dosage Regimen Design
months.
Preliminary results indicate that metabolites of An analysis of plasma tacrolimus concentra-
tacrolimus have a lower immunosuppressive activ- tions in renal transplant recipients and the inhi-
ity,140.86] but the toxicity of the metabolites is not bition of cell proliferation in mixed lymphocyte
known at this time. The data published to date are cultures by the corresponding plasma samples in-
based on methods that use monoclonal antibody or dicated 90% inhibition of lymphocytes at a plasma
the MEIA method. Though not ideal, MEIA ap- concentration of 0.8 J..lg/L (Venkataraman et aI., un-
pears to be the most suitable method at the present published observations). In agreement with this ob-
time for monitoring tacrolimus. It is clear from the servation, initially (in the majority of patients) the
literature that specific assay methods (HPLC, 12-hour trough plasma tacrolimus concentrations
monoclonal radioimmunoassay) for routine moni- were maintained at 0.5 to 2 J..lg/L; currently, the
toring of cyclosporin concentrations in patients are 12-hour trough blood tacrolimus concentrations
no better than nonspecific methods (fluorescent are maintained between 5 and 20 J..lg/L. 24-Hour
polarisation immunoassay TDX, polyclonal radio- trough concentrations are 33 to 50% lower than the
immunoassay).f 137] corresponding 12-hour trough 1eve1s.f I04 ] Concen-
trations are maintained towards the higher end of
7.4 Frequency of Tacrolimus Monitoring the range during the immediate postoperative pe-
riod, and towards the lower end subsequently.
Given the mean disposition half-life of tacro- Based on the pharmacokinetic parameters esti-
limus of around 10 hours, it is necessary to wait at mated in the study of Jain et aI.,197] an intravenous
least 36 hours (3.3 half-lives) to reach a steady- dosage regimen of tacrolimus 0.027 mg/kg/day dur-
state tacrolimus concentration after initiation of ing the immediate postoperative period is ex-
therapy or after a change in the administration reg- pected to produce a minimum steady-state plasma
imen of tacrolimus. Ideally, blood concentrations concentration of 0.8 J..lglL. Assuming an oral bio-
should be monitored on day 2 or 3 after starting the availability of 27%, the minimum oral dose of
infusion, on average 3 to 7 times weekly during the tacrolimus required to maintain a similar average
first few weeks after transplantation, and less fre- plasma concentration is 0.1 mg/kg/day. These pre-
quently thereafter. Special circumstances (changes dictions agree well with the clinical practice of
Table X. Summary of recommendation by the consensus • trough blood/plasma tacrolimus concentrations

conference on tacrolimus monitoringl1041
(very low blood concentrations of <5 J.1g/L lead
1. Regular therapeutic monitoring is essential during therapy
to dose increase; high blood concentrations of
2. Target 12·hour trough blood concentrations are 5·20 ].Ig/ml
early post-transplant. 24-hour trough concentrations are
> 20 J.1g/L lead to dose reduction).
33-50% lower A user-friendly Intelligent Dosing System
3. Whole blood with EDTA is the preferred matrix (IDS) for estimating the dose required to achieve a
4. Blood samples can be maintained for 1 week or shipped desired plasma tacrolimus concentration in liver
under ambient temperatures
and kidney transplant recipients and in patients
5. Trough blood concentration is the preferred sample for
monitoring with autoimmune disease has been developed and
6. IncStar'" ELISA offers greater sensitivity and Abbott MEIA validated.1140-1431 For dose individualisation, the
provides a faster turn around time knowledge base is updated with patient-specific
7. Irnmunoassays are nonspecific; HPLC/MS assay is specific
feedback including the current dose, drug concen-
and may be used in certain cases
8. Food decreases absorption; monitoring is important when
trations and new target concentrations.
drugs which alter cy1ochrorne P450 3A are added to or Steinmuellerl1441 has reported a model for pre-
deleted from therapy
dicting the total daily dose and modifying the ad-
9. Internal and external proficiency testing programrnes are
important for assessing the laboratory performance
ministration regimen of tacrolimus in patients. The
10. Monitoring should start on day 2 or 3, and be carried out 3- presence of a strong correlation (r= 0.583) between
to 7-times a week for the first 2 weeks, and then less often erythromycin breath test (predictor ofCYP3A activ-
unless indicated otherwise ity) and tacrolimus dose suggests possible applica-
Abbreviations: EDTA =ethylenediamine tetraacetic acid; ELISA =
enzyme-linked immunosorbent assay; HPLC = high performance
tion of this test in predicting tacrolimus dose re-
liquid chromatography; MEIA =
microparticulate enzyme quirements in patients.11451
=
immunoassay; MS mass spectrometry. The recommendations of the Consensus confer-
ence on tacrolimus monitoring are summarised in
table X. While cyclosporin and tacrolimus share a
using 0.05 mg/kg/day as the dosage by intravenous number of similar kinetic properties, there are sev-
infusion, and 0.1 to 0.3 mg/kg/day as the oral dos- eral differences between them (table Xl).
age. Given the average disposition half-life of
about 8 to 12 hours, the drug is normally adminis-
9. Conclusions
tered twice a day. In certain cases, an intravenous
and oral pharmacokinetic study may be useful in Tacrolimus is a novel immunosuppressive drug
identifying patients who absorb tacrolimus poorly with a large inter- and intraindividual variation in
from those who eliminate it very rapidly; the latter its pharmacokinetics, with variable rates and ex-
patients may benefit from administration 3 times tents of absorption, variable extents of blood pro-
daily, while patients with poor absorption may tein binding and variable rates of elimination). It is
need higher doses on a twice-daily regimen. Dose incompletely bioavailable after oral administra-
adjustments of tacrolimus are based on: tion, is bound extensively to red blood cells (the
• the clinical status of the patient (whether a pa- binding being saturable), is primarily eliminated
tient is rejecting an organ or has a drug-related by hepatic metabolism and has a narrow therapeu-
toxicity) tic index.
• the functional status of the liver (administration Tacrolimus is administered to patients whose
of a lower dose in the presence of liver dysfunc- clinical situation requires them to receive several
tion to minimise overexposure of the drug and other drugs. Monitoring of tacrolimus concentrations
resulting toxicity) in blood or plasma will help to optimise tacrolimus
• the response to a nephrotoxic event (dose reduc- therapy. Blood tacrolimus concentrations are nor-
tion if the patient experiences nephrotoxicity) mally maintained between 5 and 20 J.1g/L.
© Adis International Limited. All rights reserved. Clin. Phormacokinet. 29 (6) 1995
Table XI. Comparison of tacrolimus and cyclosporin

Condition Tacrolimus Cyclosporin
Chemical structure Macrolide Cyclic polypeptide
Solubility (aqueous) Very low, <1 mg/L Very low, <7 mg/L
Administration regimen
intravenous doses 0.05-0.1 mg/kg/day as continuous infusion 2-4 mg/kg/day as continuous infusion
oral doses 0.1-0.3 mg/kg/day bid 5-15 mg/kg/day bid
Absorption
rate Variable Variable
bioavailability, F Low (25%) Low (30%)
bile Less essential Very essential for conventional formulation, but
less essential for Neoral® (microemulsion)
formulation
Distribution
blood: plasma ratio High (15: 1) Lower (2: 1)
major binding plasma proteins u1-Acid glycoprotein Lipoproteins
Metabolism: major enzyme pathways Highly metabolised cytochrome P450 3A Highly metabolised cytochrome P450 3A
hydroxylation, demethylation, minimal hydroxylation, demethylation, conjugation
conjugation
Effects of liver disease:
intravenously administered drug ! Elimination ! Elimination
orally administered drug i Absorption ! Absorption
Effects of renal disease No change No change
Effects of haemodialysis No change in clearance No change in clearance
Excretion
parent drug Very low in urine Very low in urine
metabolites Excreted primarily in bile Excreted primarily in bile
Activity
parent drug Most active Most active
metabolites A lot less active Less active
Drug interaction profile Blood concentrations increase with enzyme Blood concentrations increase with enzyme
inhibition; inhibition;
blood concentrations decrease with enzyme blood concentrations decrease with enzyme
induction induction
Therapeutic monitoring method Blood MEIA Blood monoclonal FPINHPLC
Therapeutic range
blood 5-20 J.lg/L 100-400 J.lg/L
plasma 0.1-5 J.lg/L 50-200 J.lg/L
Abbreviations: bid = twice daily; FPINHPLC = fluorescence polarimetry immunoassay/high performance liquid chromatography; MEIA =
microparticulate enzyme immunoassay.
Currently, MEIA is the method of choice for The contribution of tacrolimus metabolites to
therapeutic monitoring of tacrolimus in blood. the toxicity and immunosuppressive activity of
However, it is desirable to develop a more sensitive tacrolimus also needs to be further evaluated.
and specific method for monitoring tacrolimus.
Our knowledge of the pharmacokinetics of tacro-
Acknowledgements
limus is incomplete at this time, primarily due to
the lack of sensitive, specific and readily available Work reported here is supported in part by USPHS grant
analytical methods. AM 33475 and a grant from the University of Pittsburgh.
with methylene chloride extraction. Ther Drug Monit 1994;

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133. Japanese FK 506 Study Group. Japanese study of FK 506 on
kidney transplantation: the benefit of monitoring the whole Department of Pharmaceutical Sciences, 718 Salk Hall,
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1991; 23: 3085-8 PA 15261, USA.
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C~n . Phormocokinet. 29 (6): 404-430.

© Adis International limited. All rights reserved.

Summary Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive

Table I. Analytical methods for measuring tacrolimus

Table III. Comparison of different methods of measuring tacrolimus

whole blood concentrations, as the concentration 10

of tacrolimus in the blood is higher than the con-

Table V. Characteristics of tacrolimus and its metabolites

recipients as unchanged tacrolimus as determined 25

by the ELISA method. Renal clearance of tacro- ::J • Blood

limus, or tacrolimus metabolites which cross-react "c

assay, is excreted in the bile. Small amounts of the .S:

The plasma and blood concentration-time pro-

Table VII. Pharmacokinetics of tacrolimus (determined using enzyme-multiplied immunoassay)

Table IX. Drug-drug interactions involving tacrolimus and other drugs

Agents that decrease tacrolimus concentrations

Agents that increase tacrolimus concentrations

© Adis Internotionoilimited. All rights reserved. elin. Pharmocokinet. 29 (6) 1995

o Blood concentration of tacrolimus 48

Table X. Summary of recommendation by the consensus • trough blood/plasma tacrolimus concentrations

Table XI. Comparison of tacrolimus and cyclosporin

with methylene chloride extraction. Ther Drug Monit 1994;

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