DRUG DISPOSITION
C~n .
Phormocokinet. 29 (6): 404-430. 1995 0312-5963/95/00 12-()4()4/S 13.50/0
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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 .... . . . . . . . 1. Dosage Forms of Tacrolimus 2. Analytical Methodology .. 2.1 Enzyme Immunoassays . 2.2 Radioreceptor Assay . . 2.3 Chromatographic/Moss Spectrometric Methods 2.4 Bioassay .. .. . . . . . . 2.5 Comparison of Methods . 2.6 The Matrix Effect 3. Pharmacokinetics . . . . . . . 3.1 Absorption . . . . . . . . . 3.2 Distribution and Protein Binding . 3.3 Metabolism . . . . . . . . . . . 3.4 Excretion . . . . . . . . . . . . . . . 3,5 Pharmacokinetic Parameters . . . 4. Factors Affecting Tacrolimus Pharmacokinetics 5. Drug Interactions , . . . . . . . . . , , 6, Treatment of Drug Toxicity/Overdose 7. Therapeutic Monitoring of Tacrolimus 7.1 Rationale for Monitoring .. , , . 7.2 Trough Concentration Monitoring 7.3 Methods/Matrix for Monitoring Tacrolimus . 7.4 Frequency of Tacrolimus Monitoring 7.5 Precautions .. . .. 8. Dosage Regimen Design 9. Conclusions . . . . . . . .
. 405 . 405 · 406 · 406 · 407 · 408 · 409 . 409 · 410 · 410 .411 · 412 .414 . 416 · 417 · 418 . 419 · 421 · 421 · 421 · 423 423 · 424 , 424 , 424 , 425
Tacrolimus Clinical Pharmacokinetics
Summary
405
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. Currently, 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 elimination 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 variability, 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 (fig. 1) with potent immunosuppressive properties)') It has been in clinical use in Japan since 1993, and was approved in the US in April 1994 for the prophylaxis of organ rejection after liver transplantation. Tacrolimus is also effective in preventing graft rejection in heart, small bowel and kidney transplant recipients. [2.3) The role of tacrolimus therapy in several autoimmune diseases is currently being evaluated. Tacrolimus is a very lipophilic compound with a molecular weight of 804, existing as a monohydrate in the solid state. It is highly soluble in methanol , chloroform, acetone and ethyl acetate, soluble in ethyl ether, propylene glycol and polyethylene 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 © Adis International Limited. All rights reserved.
alkaline conditions. At the present time, these properties make it difficult to formulate tacrolimus into an ideal dosage form for patient use.
12
H3CO 0
H3CO ·.•. 15
H3C·· ..
V
N
4
2 3
18
CH3# 20
o
Fig. 1. Structure of tacrolimus.
Clin. Pharmacokinet. 29 (6) 1995
Venkataramanan et al.
406
1. Dosage Forms of Tacrolimus Tacrolimus is currently available for intravenous administration as a solution containing tacrolimus, alcohol and a surfactant (HCO-16). The potential for anaphylactic reactions due to the presence of a surfactant in the intravenous formulation should be borne in mind while using this formulation in patients. The intravenous formulation (5 mg/ml) must be diluted in 5% dextrose or normal saline and administered as a continuous infusion over 24 hours to minimise the nephrotoxicity of the drug. When diluted in dextrose or normal saline, tacrolimus is stable for at least 24 hours and is completely available from (i.e. not adsorbed onto) plastic syringes, glass and polyolefin containers.l 51 Certain intravenous administration sets, such as Venoset and Accuset, can adsorb significant amounts of tacrolimus from the intravenous solution and their use may lead to a lower dose of tacrolimus being delivered to patients.l6] The oral dosage form of tacrolimus is available as Img and 5mg capsules of a solid dispersion of tacrolimus in hydroxypropylmethylcellulose. Several additional formulations are currently being evaluated. A liposomal tacrolimus formulation has been reported to provide better immunosuppression in rats, compared with the currently available intravenous formulation, in spite of achieving similar blood concentrations of tacrolimusp,8)It has been suggested that it may also be less nephrotoxic and neurotoxic than the currently available intravenous formulation, because of reduced accumulation of tacrolimus in the kidney and the brain of rats treated with the liposomal formulation. Another liposomal formulation with good in vitro stability, prolonged disposition and immunosuppressive activity similar to that of free drug has also been reported)91
2. Analytical Methodology Tacrolimus is stable in whole blood specimens for about 1 year at -70'C, for at least 2 weeks at 4'C and 22°C,[101 and for at least 2 to 3 days at 37'C.l111 Tacrolimus concentrations in biological © Adis International Limited. All rights reserved.
fluids have been measured using a number of methods (table I). However, the development of a simple, specific and sensitive assay method for measuring tacrolimus in biological fluids is limited by: • the low absorptivity of tacrolimus • the low concentrations of tacrolimus in plasmal blood, and • the presence of several other drugs in the blood samples obtained from transplant patients, which potentially interfere with the analysis of tacrolimus. The analytical methods available for measuring tacrolimus in biological fluids have been summarised previously,l32,491 The currently available assays can be broadly classified as enzyme immunoassays, a radioreceptor assay, chromatographic/ mass spectrometric assays and a bioassay. 2.1 Enzyme Immunoassays
In 1987, Tamura et aU121 reported the first method for quantitation of tacrolimus in plasma using an enzyme-linked immunosorbent assay (ELISA) method following a solid-phase extraction procedure to separate tacrolimus from other components in the sample. The clinical application of this assay was first reported in 1990,(13) and a modification of this method has been used to measure tacrolimus in whole blood.l 14 ,34) A unified method of extraction of whole blood and plasma using methylene chloride was reported by Kobayashi et al. in 1991,(16) while ethyl acetate has also been used for the extraction of tacrolimus from blood, tissue and plasma,l351 Although the results obtained after methylene chloride extraction and the solid-phase extraction procedures correlate well with each other (r2 = 0.91), the solid-phase extraction method consistently yields higher estimates (about 42%), in comparison with the procedure that uses methylene chloride for extraction.l 161 A number of drugs (see table II) used to treat transplant patients do not appear to cross-react with the antibody used in the ELISA procedure.[14-161 The IncStar PRO-TRAC@ ELISA method that uses the same anti-FK506 monoclonal antibody as that used in the ELISA method described above Clin. Pharmacokinet. 29 (6) 1995
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Tacrolimus Clinical Pharmacokinetics
Table I. Analytical methods for measuring tacrolimus Assay
Biological Extraction fluid
Detection
Sample volume (~I)
ELISA ELISA
Plasma
Benzene
Colourimetric
100
Plasma
Solid phase
Colourimetric
100
24
0.1-5
ELISA
Plasma
Solid phase
Colourimetric
100
ELISA
Plasma
Solid phase
Colourimetric
100
8 6 8 8
O.HO O.HO O.HO O.HO
24 8
0.2-10 0.1-8
11
8
O.HO
32
8
0.8-80 3-75
13 8
0.8-64 0.8-80 1.0-120
20 17
ELISA
Plasma
Liquid
Colourimetric
100
ELISA
Plasma
Liquid
Colourimetric
300
ELISA ELISA ELISA ELISA
Plasma Plasma
Liquid Liquid
Colourimetric Colourimetric
300
Plasma Blood Blood
Solid phase Solid phase Solid phase
Colourimetric Colourimetric Colourimetric
25 25
Blood Blood
Liquid Liquid
Colourimetric Colourimetric
25 10
ELISA
Blood Blood
Liquid Liquid
Colourimetric Colourimetric
20 20
ELISA
Blood
Liquid
ELISA
Blood
20 50
MEIAlIMX
Blood
MEIAlIMX MEIAlIMX
Blood Blood
MEIAlIMX HPLC-ELISA HPLC-ELISA
Blood
Solid phaselliquid No extraction No extraction No extraction No extraction
Colourimetric Colourimetric Colourimetric Colourimetric Colourimetric Colourimetric
Serum Plasma
HPLC-ELISA
Blood
HPLC-CL
Plasma
Solid phase Solid phase/ HPLC Solid phase/ HPLC Liquid/solid phase
HPLC-MS
Blood
Solid phase/ HPLC
Bioassay Radio receptor ELISA HPL-fluorescent
Plasma Blood Blood Blood
ELISA ELISA ELISA ELISA
a b
100 100
Periormance Linearity" Reproducibilityb time (h) (mg/L) intraday interday 0.02-10
6 8 8 8 24 24-30
12
23 27
Reference 12 13
7
17
14
9
17
15
11
8
23 16 17 35 14 16 13
16 17 18 19 20 14 15 19 16 17
1.0-120
18
21
18
2-80
10
14
21
8
0.5-50
21
28
20
100 100 100 100
0.75 0.6 0.75
10
11.8 16
22 21 23
9
15
Colourimetric Colourimetric
200 200
24 24
5-60 5-60 10-70 5-60 0.10.1-10
12
29
20 24
17
25
Colourimetric
200
24
0.8-64.0
14
19
Derivatisation
100
24
5-1000
8
8
26
MS
1000
24
0.25-225
11
12
27
PLT-inhibition 100 72 Solid phase Radioactivity 200 6 Methanol Colourimetric 25 4 Liquid/HPLC Fluorescence 1000 24 Lower end of linearity range is accepted as the minimum detectable quantity. Highest coefficient of variation of this assay reported rounded to a whole number.
0.02-0.1
<5.0
1-25 0.5-60 0.5-200
9 11
11.5
28 9
29
15
30 31
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 to the microparticulate enzyme immunoassay (MEIA) method (see below»)34J It is more sensitive than the MEIA method, but requires more time to perform. [30J A semi-automated technique, based on the principle of MEIA for the IMX analyser developed by © Adis International Limited. All rights reserved.
Abbott, that measures the concentrations of tacrolimus in whole blood has been reported. [22] This method is not sufficiently sensitive to measure low blood concentrations of tacrolimus, and is also not completely specific to tacrolimus; a more sensitive MEIA assay is currently under evaluation. However, the existing MEIA method is Clin. Pharmacokinet. 29 (6) 1995
Venkataramanan et al.
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Table II. Drugs which do not appear to cross-react with the antibody used in enzyme-linked immunosorbent assay (ELlSA)114'16) Amikacin Amphotericin B Azathioprine Carbamazepine Cyclosporin Digitoxin Digoxin Disopyramide Erythromycin Ethosuximide Flecainide Fluconazole Gentamycin Lidocaine (lignocaine) Methylprednisolone
Netilmicin Nifedipine Paracetamol (acetaminophen) Phenobarbital (phenobarbitone) Phenytoin Prednisolone Primidone Procainamide Quinidine Salicylates Theophylline Tobramycin Valproic acid Vancomycin
rapid and simple, and an interlaboratory quality assurance programme has been established to ensure consistency of data generated from different transplant centres.[17.18] 2.2 Radioreceptor Assay
In the radioreceptor assay, tacrolimus extracted from the blood sample competes with tritiated dihydro-tacrolimus for binding to a partially purified preparation of FK binding protein (FKBP),l291 This assay is simple to perform, requires a small volume of blood and can provide a rapid turnaround time. The results of this assay correlate well with whole blood ELISA assay (r2 = 0.97). However, consistently higher tacrolimus concentrations are estimated by this assay in comparison with the ELISA, indicating that the assay is nonspecific. It is not clear whether the affinity of a molecule towards FKBP is related to the immunosuppressive activity of that molecule. Any further development of the radio receptor assay depends on establishing a relationship between the factors mentioned above. 2.3 Chromatographic/Mass Spectrometric Methods
In order to improve the specificity of the ELISA, a solid-phase extraction and a high performance liquid chromatographic (HPLC) separation and fractionation of various components in the biological fluid prior to the application of ELISA has been © Adis International Limited. All rights reserved.
evaluated. The trough plasma or blood tacrolimus concentrations as determined by ELISA and HPLC-ELISA are similar in patients with normal liver function and in patients with variable kidney function, indicating the lack of accumulation of any metabolites cross-reacting with the antibody used in the assay in plasma/blood of these patients.[14] The HPLC-ELISA procedures have, however, identified the presence of component(s) that cross-react with the antibody used in the ELISA in the serum of several paediatric liver transplant patients[24] and in the plasma of adult liver transplant patients with poor liver function ,l 14] Recently, an HPLC-MEIAassay has been developed to measure blood tacrolimus concentrations,l 361 This method involves chromatographic separation of the various components in the blood extract, followed by the application of MEIA to quantitate tacrolimus in the fraction isolated. Tacrolimus concentrations in renal and liver transplant patients measured by the direct MEIA method have been reported to be 19 to 48% higher than the concentrations measured by the HPLC-MEIA method, indicating a significant cross-reactivity of some of the metabolites of tacrolimus in the blood samples with the antibody used in the MEIA assay. An HPLC assay method with chemiluminescence detection (derivatisation with dansyl hydrazine) to measure the concentration oftacrolimus in serum and lymph of rats has been reported.[ 261This method requires a column-switching system for HPLC, and is not readily reproducible. A modification of this method (liquid extraction and on-column clean up) with fluorescent detection has been recently reported for the measurement of tacrolimus in whole blood samples.[3)] An HPLC-mass spectrometric (HPLC-MS) method for measuring tacrolimus and its metabolites in patient's blood, bile and urine samples is also available.[27.37.381 This method involves solidphase extraction of the biological samples and the use of HPLC to separate various components, followed by the use of a mass spectrometer as a detector. While the HPLC-MS assay is highly specific and sensitive, the lack of routine availability Clin. Pharmacokinet. 29 (6) 1995
409
Tacrolimus Clinical Pharmacokinetics
Table III. Comparison of different methods of measuring tacrolimus Methods
Matrix
Transplant population
r2
Conversion factor y= mx+b
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
24
20
20
20
20
=0.08x + 0.08
Temperature separation (C)
No. of specimens
Reference
MC vsSP
Plasma
Liver
0.41
y
MC vsSP
Blood
Liver
0.79
y = 0.6x + 2.0
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, bone marrow
0.81
y=0.9x+0.7
853
21
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 the difficulty in analysing a large volume of samples on a regular basis, limit the use of this technique to pharmacokinetic and metabolism studies at the present time. The absence of any significant correlation between the concentration of tacrolimus in whole blood, as measured by HPLC-MS, and in plasma, as measured by ELISA, has been reportedP7 1 Recently, a simplified HPLC-MS assay has been reported for measuring tacrolimus in whole blood and urine samples,l391 In contrast to previous reports, cross-validation of this assay with the MEIA method showed a significant correlation between the 2 assay methods (r =0.915). 2.4 Bioassay
A biological assay based on inhibition of the alloantigen-driven proliferation of a clone of alloreactive T cells has been reported by Zeevi et al.[ 28 1 While this assay provides the tacrolimus equivalent (any metabolites with activity being measured as tacrolimus) in a biological specimen, based on a bioassay, the limitations of this proce© Adis International limited. All rights reserved.
dure are the slow turnaround time (> 72 hours) involved and the inability to directly assay whole blood samples. 2.5 Comparison of Methods
A comparison of different methods of measuring tacrolimus is given in table III. A comparison of the SepPak®-ELISA method with the bioassay method for plasma indicates a significant correlation, but consistently higher estimates of tacrolimus by the ELISA method. This observation suggests that metabolites of tacrolimus cross-react with the antibody used in ELISA,l2gj Corticosteroid use and poor liver function appear to magnify the differences between these 2 assays.l28,401 While the low tacrolimus concentration estimates from bioassay were predictive of the growth of lymphocytes from liver biopsies, SepPak®-ELISA could not discriminate between those biopsy samples from which lymphocytes can be grown and those samples from which they cannot be grown.[41] The blood concentrations of tacrolimus as measured by MEIA have been reported to correlate Clin. Pharmacokinet. 29 (6) 1995
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well with those of the ELISA method;121,23,34] both methods are nonspecific, as they also measure some of the metabolites of tacrolimus. A method which uses HPLC prior to ELISA, MEIA or a mass spectrometric method is specific for the parent tacrolimus molecule. Other methods seem to measure additional tacrolimus-related components in blood or plasma, owing to the nonspecificity of the monoclonal antibody used. Larger discrepancies between different methods are observed in blood samples obtained from patients with impaired liver function, indicating the accumulation of some metabolites of tacrolimus which cross-react with the antibody used in the assay procedure. 124 ,25,36 1 The blood concentrations of tacrolimus as measured by the MEIA method do not correlate well with plasma concentrations as measured by the SepPak®-EIA method I19 ,34] and, therefore, are not interconvertible by using a simple factor. Of the 2 assay methods currently used clinically to measure the blood concentrations of tacrolimus (PRO-TRAC® ELISA and MEIA), the ELISA method generally tends to have a higher coefficient of variation than the MEIA method, while the MEl A method lacks the sensitivity required for routine clinical use. There is a need for the development of an improved assay procedure that would be of greater clinical use.
2.6 The Matrix Effect The whole blood concentrations of tacrolimus are significantly higher compared with the corresponding plasma concentrations, independent of the method of analysis of tacrolimus. It is also clear that one cannot extrapolate blood concentrations from a measurement of plasma concentrations in transplant recipients, due to variable slopes and poor correlations between the 2 variables. These results are summarised in table IV.
3. Pharmacokinetics Currently, most of the pharmacokinetic data available for tacrolimus are based on an ELISA analysis of blood or plasma samples that simultaneously measures some of the metabolites of tacrolimus. The pharmacokinetic parameters derived for tacrolimus are a function of the biological fluid analysed (significant differences exist between the blood, plasma and serum concentrations of the drug), the analytical methods used to measure tacrolimus concentrations (specific or nonspecific) and the duration of study (I administration interval vs single-dose studies). Pharmacokinetic parameters such as clearance and volume of distribution based on plasma concentrations will be higher than the clearance and volume of distribution based on
Table IV. Comparison of different methods for measuring tacrolimus (blood vs plasma) concentrations Methods
Transplant population
Temperature separation (C)
No. of specimens
Equation y = mx+b
r2
Reference
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.
© Adis International limited. All rights reserved.
Clin. Pharmacokinet. 29 (6) 1995
411
Tacrolimus Clinical Pharmacokinetics
whole blood concentrations, as the concentration of tacrolimus in the blood is higher than the concentration of tacrolimus in plasma. On the other hand, pharmacokinetic parameters such as clearance and volume of distribution will be underestimated when a nonspecific assay method (ELISA, MEIA) is used in comparison with the parameters derived based on a specific assay method (HPLCMEIA, HPLC-MS). Studies involving blood sampling over a dose interval (normally 12 hours) that is less than or equal to 1 terminal disposition half-life provide smaller half-life estimates compared with a singledose kinetic study, in which blood samples are collected over multiple half-lives, and the terminal disposition half-life can be more precisely estimated)42] The above information must be borne in mind when interpreting the available kinetic data for tacrolimus. The pharmacokinetics of tacrolimus have previously been summarised by Venkataramanan et aI.,[43-45] Peters et aI.,[46] Hooks,[47] Steinmiiller,[48] Venkataramanan and Warty[49] and Kelly et aJ.l50] Tacrolimus is primarily used in transplant patients who receive an organ that is either involved in the absorption (small bowel) or elimination (liver) of the drug. The physiological status of the organs transplanted is expected to influence the absorption (small bowel recipients), distribution (all transplant patients) and metabolism (all transplant patients) of tacrolimus. Time-dependent changes in the absorption, distribution and metabolism of tacrolimus are also anticipated in patients receiving tacrolimus therapy (time-dependent haematocrit and plasma protein concentration changes altering the distribution, and time-dependent changes in the activity of the liver enzymes responsible for the metabolism of tacrolimus altering the elimination). 3.1 Absorption
Tacrolimus is absorbed rapidly in most patients, with peak plasma/blood concentrations being reached in about 0.5 to 1 hour, while in others the drug is absorbed slowly over a prolonged period, yielding essentially a flat absorption profile (fig. © Adis International Limited. All rights reserved.
10
:::Ja
~c
o ~6
'E Q) ()
c
8
4
(1)
E
'" £2 2
4
6 Time (h)
a
10
12
Fig. 2. Tacrolimus plasma concentration-time profile after a 5mg dose given orally to 5 different liver transplant patients. Different symbols represent different patients.
2))42-44,49,51] A lag time of 0 to 2 hours has also been reported in some liver transplant recipients.[51] Poor aqueous solubility of tacrolimus (and therefore dissolution rate-limited absorption) and alterations in gut motility in transplant patients may account for these observations. The shape of the plasma concentration-time profile in some patients (sharp peaks), and the higher dose-normalised maximum blood concentration (Cb,max) at lower doses that is seen in some patients who received different doses, are suggestive of the involvement of a zero order/saturable process in the absorption of tacrolimus[52J (Venkataraman et aI., unpublished observations). Accordingly, the uptake of tacrolimus in the rat intestinal ring has been shown to be a saturable process.[53] These results would then suggest that it may be better to administer the daily dose of tacrolimus in multiple divided doses to increase the overall exposure of the patients to the drug. The oral bioavailability of tacrolimus is poor and ranges from 4 to 89% (mean of around 25%) in kidney and liver transplant recipients and in patients with renal impairment)42,44,51,54-56] The bioavailability of tacrolimus is similar in small-bowel transplant recipients with a closed stoma; however, the bioavailability of tacrolimus is lower in patients Clin. PhOrmacokinet. 29 (6) 1995
412
with open stoma compared with those with closed stoma. L57 ] Unusually high bioavailability (89% and 93%) was observed in I small-bowel transplant patient on 2 separate occasions. The specific reasons are not clear at this time. The rate of absorption and the bioavailability of tacrolimus after oral administration appear to be variable in all the patient populations studied, irrespective of the organ transplanted. In general, oral doses of tacrolimus should be 3 to 4 times higher than intravenous doses to achieve comparable drug exposure after oral and intravenous administration. Based on the low blood clearance of tacrolimus, it can be predicted that the low bioavailability of tacrolimus is either due to gut metabolism or to poor oral absorption of the drug. Incomplete absorption of tacrolimus is largely responsible for the low bioavailability of tacrolimus in rats.l 58 ] Increased availability of tacrolimus from a solution dosage form of tacrolimus in comparison with the currently available solid dispersion formulation, also supports this hypothesis (Venkataraman et aI., unpublished observations). On the other hand, metabolism of tacrolimus by microsomes obtained from dog jejunum supports the potential involvement of gut metabolism in reducing the oral bioavailability of tacrolimus (Venkataraman et aI., unpublished observations). Tacrolimus is bioavailable to a similar extent in paediatric and adult transplant patients[56] (Venkataraman et aI., unpublished observations). Tacrolimus, however, is poorly bioavailable in patients awaiting renal transplantation (mean bioavailability of 14 ± 12%; range 6 to 36%).[42] This observation is of importance in oral administration of tacrolimus during the immediate postoperative period. In contrast to what is known about cyclosporin, clamping of the T-tube in liver transplant recipients does not alter the trough concentrations or area under the plasma concentration-time curve (AUC) of tacrolimus.l 44 ,59] This implies that there is no need to change the dose of tacrolimus when the T-tube is clamped in a liver transplant recipient. Complete biliary diversion or addition of bile salts appear to have no significant effect on the oral bioavailabil© Adis International Limited. All rights reserved .
Venkataramanan et al.
ity of the solid dispersion of tacrolimus in dogs.l 60] Due to the lack of any effect of bile on the bioavailability of tacrolimus, overlap of intravenous and oral tacrolimus therapy is not necessary in liver transplant patients, as is the case with cyclosporin. This means that tacrolimus has a particular advantage over cyclosporin in liver transplant recipients. 3.2 Distribution and Protein Binding
In transplant recipients, the blood tacrolimus concentration is significantly higher (average 15 times; range 4 to 114 times) than the corresponding plasma concentrations.[14,17,35,43,51,61,62] This is due to the extensive binding of tacrolimus to the red blood cells [maximum amount bound (Bmax) = 418 ± 258 ~glL and apparent dissociation constant (K D) =3.8 ± 4.7 ~glLin transplant patients; Bmax = 1127 ~g/L and KD = 13.5 ~glL in healthy adults]. The reasons for the differences between healthy adults and transplant patients are not clear at this time. The diffusion oftacrolimus from erythrocytes is slow in comparison with the transit time of blood through an organ, but tacrolimus is readily released from the erythrocytes,[63.65] and the binding of tacrolimus to erythrocytes may in part protect it from hepatic metabolism.l69 ] Tacrolimus does not bind to haemoglobin. An intracellular protein in erythrocytes , with a molecular weight range (14 to 15kD) corresponding to FKBP,[63] or a molecular weight of 11 to 12kD[67] appears to be primarily responsible for binding tacrolimus. As the concentration of tacrolimus increases in whole blood, the uptake of tacrolimus by erythrocytes is saturated, resulting in a lower blood: plasma ratio.l 17 ,63,65,67] In human plasma, most of the tacrolimus is associated with the lipoprotein-deficient fraction. Unlike cyclosporin, tacrolimus does not significantly associate with the lipoprotein fraction in plasma.l44 ,63,67,68] Nearly 72 to 77% of the drug in the plasma is bound to plasma proteins, as determined by ultracentrifugation.l 63 ,66] In contrast, a higher extent of binding (98.8%) of tacrolimus in human plasma has been reported, based on ultrafiltration studies.l67 ] This observation may in fact reflect an artefact of the methodology (nonspecific Clin. Pharmacokinet. 29 (6) 1995
413
Tacrolimus Clinical Pharmacokinetics
Table V. Characteristics of tacrolimus and its metabolites Identified in:
Immunecross-reactivity
804 790
ICso (mg/L) 0.11 1.71
15·G-Demethyl·tacrolimus (Mil)
790
>1000d
90.5
31-G-Demethyl-tacrolimus (MIII)C
790
41lg/mld 0.11
Liver microsomal system (rat, baboon, human); blood & urine (human)
109.0
Liver microsomal system (rat, baboon, human); blood & urine (human)
13,15-G-Didemethyl-tacrolimus (MIV)
776
>1000
Nil
13,31-G-Didemethyl-tacrolimus (MV)
776
8.78
Nil
15,31-G-didemethyl-tacrolimus (MVI)
776
>1000d 325d
92.2
Metabolite of tacrolimus with a 10-membered ring (MVII) 14-Hydroxy-tacrolimus (MVIII)
821
15.27
Nil
Liver microsomal system human) Liver microsomal system blood & urine (human) Liver microsomal system blood & urine (human) Liver microsomal system
820
3.13
8.8
Epoxide of tacrolimus (MIX)
820
Plasma (human)
Dihydroxydiol of tacrolimus (MX)
838
Liver microsomal system (baboon); plasma (human)
Dihydroxylated tacrolimus (MXI) Dihydroxydiol of tacrolimus with a 7-membered ether ring (MXII)
836 854
Plasma (human)
Parent drug/metabolite (code name)
Molecular weight"
Tacrolimus 13·G-Demethyl·tacrolimus (MI)b
Tetrol of tacrolimus (MXIII) 872 Tri-demethylated, hydroxylated 794 tacrolimus epoxide (MXIV) Di-demethylated, hydroxylated 792 tacrolimus (MXV) Phase II metabolites' a From mass spectrometry, mass/charge (MIZ). b Major metabolite.
100 Nil
Liver microsomal system (rat, baboon, human, rabbit); blood & urine (human)
(rat, baboon); (rat)
Plasma (human) Plasma (human) Liver microsomal system (rabbit) Liver microsomal system (baboon); bile (human) Bile (rat, human)
Active metabolite. Different results were reported, perhaps related to differences in solubility of metabolites.
e
Venkataraman et aI., unpublished observations.
© Adis International Limited. All rights reserved.
(rat, baboon);
Liver microsomal system (rat, baboon); bile (human)
c d
adsorption onto the devices) used. Equilibrium dialysis and ultrafiltration are not suitable for evaluating the protein binding of tacrolimus because of adsorption of tacrolimus onto the membranesJ63] The plasma protein binding of tacrolimus is not saturated up to 50 Ilg/L, but is saturable at higher concentrations. Tacrolimus is primarily associated with ai-acid glycoprotein (AAG), an acutephase protein. I16.63.671 and albumin.[661
(rat, baboon,
The partitioning of tacrolimus between erythrocytes and plasma is dependent on the concentration of tacrolimus, haematocrit, sample temperature and concentration of plasma proteins responsible for tacrolimus bindingJ35,62,63,65,67 1 Alterations in these variables will influence the relative distribution of tacrolimus between blood cells and plasma. It is well known that haematocrit increases with time after transplantation in renal transplant recipients. This will tend to increase the blood: plasma Clin. Pharmacokinet. 29 (6) 1995
Venkataramanan et al.
414
ratio of tacrolimus in these patients. 162 ,63,67] At sample temperatures of up to 25°C, there is no difference in the distribution of tacrolimus within the blood. However, at higher temperatures, relatively more drug stays in the plasma compartment. 162 ,63,67] The concentration of AAG in plasma is also known to increase with time after transplantation. An increase in AAG concentration leads to a significant increase in binding of tacrolimus in plasma. This tends to decrease the blood: plasma ratio of tacrolimus. 163 ] Cyclosporin does not have any effect on protein binding of tacrolimus. The uptake oftacrolimus by lymphocytes is also saturable.(70,71] A cytosolic protein with a molecular weight range of 18 to 19kD appears to be responTable VI. Involvement of cytochrome P450 (CYP) in tacrolimus metabolism A. Involvement of CYP3A 1. Significant correlation between tacrolimus metabolism and nifedipine oxidation in human liver microsomesl811 2.
Significant correlation between CYP3A4 activity (testosterone 6-~-hydroxylation) and tacrolimus metabolism l871
3.
Metabolism of tacrolimus by reconstituted human CYP3A4181.871
4.
Inhibition of tacrolimus metabolism by anti-CYP3A4 antibodiesl81 .831
5.
Inhibition of tacrolimus metabolism by troleondomycin, gestodene and several CYP3A substratesI81.87.93.941
6.
Induction of tacrolimus metabolism by dexamethasoneI81 .89.931
7.
Lack of induction of tacrolimus metabolism by phenobarbital and 3-methyl cholanthrenel931
B. Involvement of additional subsets of CYP in the metabolism of tacrolimus 1. Only partial inhibition of tacrolimus metabolism by anti-CYP3A antibodies l831 2.
Inhibition of tacrolimus metabolism by anti-CYP1A antibodyl831
3.
Inhibition of tacrolimus metabolism by 7,8-benzoflavoneI831
4.
Significant correlation between tacrolimus metabolism and chlorzoxazone hydroxylation (CYP2E1) and 7-ethoxycoumarin demethylation (CYP2A6) in vitrd811
5.
Inhibition of tacrolimus metabolism by quinidine, a specific inhibitor of CYP2D6 and debrisoquine, a substrate for CYP2D6187.941
6.
Metabolism of tacrolimus in untreated female rats showing no classical CYP3A activityl891
© Adis International Limited. All rights reserved.
sible for the binding of tacrolimus in lymphocytes. It has been reported that the actual concentration of tacrolimus per cell is greater in lymphocytes than in red blood cells. 167 ] Tacrolimus accumulates in high concentrations in organs such as lungs, spleen, heart, kidney, pancreas, brain, muscle and liver, in comparison with blood or plasma, of rats and monkeys.l72,73] So far, the presence of tacrolimus in cerebrospinal fluid has not been documented, even in patients with tacrolimus-induced neurotoxicity (Venkataraman et aI., unpublished observations). Tacrolimus appears to pass through the placenta and reach the fetal circulation. The concentration of tacrolimus in umbilical cord plasma is about 350/0 of the corresponding maternal tacrolimus plasma con centration;l74] hyperkalaemia has been observed in some neonates, and renal impairment was reported in 1 baby immediately after birth, but this resolved with time. 174 ] The placenta tends to accumulate tacrolimus as demonstrated by the fact that placental concentrations are 4 times greater than maternal plasma concentrations. The concentration of tacrolimus in breast milk is similar to the plasma concentration. Even though the baby is expected to be exposed to a very low dose of tacrolimus, breastfeeding is currently not recommended in patients who are on tacrolimus therapy.
3.3 Metabolism
Tacrolimus is primarily eliminated from the body as several metabolites. Although the liver is the primary site of metabolism, there is direct and indirect evidence for the involvement of the gut in tacrolimus metabolism I37 ,60] (Venkataraman et aI., unpublished observations). Tacrolimus metabolites have been isolated from human plasma and bile, rat bile, and liver microsomes obtained from humans, rats, rabbits and baboons,127,37,38,75-90] (table V). While human and baboon livers are highly efficient in metabolising tacrolimus, other species metabolise tacrolimus at a slower rate.l 91 ] Tacrolimus is converted to at least 15 metabolites (fig. 3). Clin. Pharmacokinet. 29 (6) 1995
~
e
':(5
~
~
g
~:r
Q
0.
~
~
or
:J"
,6-
~
0.
~
~
Q.
o:J
~
iii
S"
~
6>
_j
~
1
MFO
1
f
~
cytochrome P450; IMR
I
mixed function oxidase.
Dihydrodiol 01 tacrolimus with 8-membered ether ring Molecular weight = 854
~
~
'0
~ Dihydrodiol of tacrolimus Molecular weight = 838
intramolecular rearrangement; MFO
3\\Ofl Gofl\',}g
Hydrase
14-Hydroxylated tacrolimus Molecular weight" 820
Molecular weight" 790
Epoxide of tacrollmus Molecular weight" 820
13-Demethyl-tacrollmus 15-Demethyl-tacrolimus 31- Demethyl-tacrol imus
I"
I
Hydroxylated tacrollmus Molecular weight" 820
Conjugates in bile or urine
~
J
.§
(J
..
~ €
c:
2
""....
CYP4503A4?
Demethylallon
Hydroxylated tacrolimus Molecular weight" 820
Conjugation
C'o~£< :9~~o"
MFO
31-Demethyl-tacrolimus; Molecular weight = 790
Molecular weight" n6 ..
I
Fig_ 3_ Metabolic pathway of tacrolimus. Abbreviations and symbols: CYP
Dihydroxylated tacrolimus with 7-membered ether ring Molecular weight" 836
~
~
~
~
~
jg
tl
9 .s
Metabolite of tacrolimus with 10-membered ring Molecular weight = 821
13,15-DemethyHacrolimUS 15,31-Demethyl-tacrolimus 15,31-Demethyl-tacrolimus
r'>
.... "'<.n"
r'> V>
~.
~
r'>
'"o
'" 9
::T
'"0
e:.
r'>
[
(J
V>
c
§"
a
;;?
Venkataramanan et al.
416
12 11
::11
~c
9
.~
8
o
o
Intravenous administration
•
Oral administration
C
g7
8(/)
6
s: "2
5
~
4
'~"
3
:::l
u
a::'"
2
O~-r-r---r---.---.---.---.---'---'---'---'---'---'---4 10 12 14 16 18 20 22 24 26 2 6 8 Time (h)
o
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 metabolism of tacrolimus was confirmed by measuring the formation of adrenochrome, which indicates the formation of oxygen radicals.1921 There is strong evidence to suggest that cytochrome P450 (CYP) 3A4 is involved in the metabolism of tacrolimus.l 81 ,83,93 1 The evidence for this, and for the involvement of other isoenzymes in the metabolism of tacrolimus, is summarised in table VI. Hydroxylation and demethylation appear to be the major metabolic pathways involved (see fig. 3), 13-0-Demethyl-tacrolimus appears to be the major metabolite of tacrolimus in human liver microsomesl 83 ] and in patient blood. 127 ,751 Five metabolites (a dihydrodiol, a dihydrodiol with a 7membered ring ether structure, a dihydrodiol with an 8-membered ether ring structure, a tetrol and a dihydroxy derivative of tacrolimus) have been identified in human plasma,f76] Five metabolites (demethyl-, demethylhydroxy-, didemethyl-, didemethylhydroxy-, and hydroxy-tacrolimus) have been reported in blood samples obtained from liver transplant and renal transplant recipients,[95] with the demethyl (approximately 3% of the AUC of © Adis International Limited. All rights reserved.
tacrolimus) and demethylhydroxy metabolites (approximately 10% of the AUC of tacrolimus) being the major metabolites.l 96 ] In urine, demethyltacrolimus was the primary metabolite. The immunosuppressive activity of 31-0-demethyl-tacrolimus was comparable to that of tacrolimus, but this metabolite has not been reported in the human blood so far. 13-0-Demethyl-tacrolimus has been observed in blood, and is approximately one-tenth as active as tacrolimus in a mixed mouse lymphocyte reaction, while the other metabolites had little or no activity,185,86] The immuno-cross-reactivity of 31O-demethyl-tacrolimus, 15-0-demethyl-tacrolimus and 15.31-0-didemethyl-tacrolimus with the mouse anti-tacrolimus monoclonal antibody used in the ELISA assay were comparable to that with tacrolimus,186] More studies are needed to evaluate the potential contribution of the metabolites of tacrolimus to the immunological and toxic effects observed after tacrolimus therapy, 3,4 Excretion
Less than I % of the intravenous dose of tacrolimus is excreted in the urine of liver transplant elin. Pharmacokinet. 29 (6) 1995
417
Tacrolimus Clinical Pharmacokinetics
recipients as unchanged tacrolimus as determined by the ELISA method. Renal clearance of tacrolimus is less than I % of total body clearance.[441 A small amount of tacrolimus conjugate also appears in the urine.[821 Less than 1% of unchanged tacrolimus, or tacrolimus metabolites which cross-react with the monoclonal antibody used in the ELISA assay, is excreted in the bile. Small amounts of the conjugates of tacrolimus or its metabolites appear in the bile. Animal studies using radioactive tacrolimus indicate that biliary excretion is the major pathway of excretion of tacrolimus metabolites. 1581
The plasma and blood concentration-time profile of tacrolimus after a short infusion (4 hours) are shown in figures 4 and 5. Figure 6 illustrates the blood and plasma concentrations of tacrolimus after continuous intravenous infusion in a liver transplant recipient. A 2-compartment model seems to adequately describe the concentrationtime profile.l42.971 A I-compartment model with nonlinear binding to red blood cells has also been used to describe the tacrolimus plasma concentration-time profile after intravenous infusion. [51] The various pharmacokinetic parameters of tacrolimus are summarised in tables VII and VIII. • Oral • Intravenous
0;-----,----.-----.----.-----.----,
o
2
4
6
8
10
12
Time (h) Fig. 5. Blood concentrations (logarithmic scale) of tacrolimus in a liver transplant recipient after oral administration on day 1 and after a short intravenous infusion on the following day.
© Adis International Limited. All rights reserved.
• Blood • Plasma
0,
.320 c 0
~c 15 "c Q)
810 rJ)
:::l
.S:
e "'"
5
I-
0 0
5
10
15
20
25
Time (h) Fig. 6. Tacrolimus plasma and whole blood concentration-time profile after continuous IV infusion (0.15 mg/kg/day) in a liver transplant recipient.
3.5 Pharmacokinetic Parameters
2
25 ::J
The mean terminal disposition half-life of tacrolimus has been reported to be 8.7 hours,[72] 11.3 hours,[43- 45 1 12.1 hours,[51] 26 hours,[96] 32 hours 1103 ] and 32.5 hours.[42] Typically, short halflives have been reported in studies carried out in patients during 1 administration interval (normally 12 hours), while long half-lives have been reported in transplant recipients, nontransplant patients and in healthy people who received a single dose and/or who were studied for 72 hours after a dose. The lower half-life estimate obtained in transplant recipients, however, is consistent with the observation that near-steady-state blood concentrations are reached in most patients within 36 to 48 hours of administration of tacrolimus . 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 tacrolimus is in fact a low-clearance drug (blood clearance of about 6 Llh). In liver transplant recipients, there was an apparent correlation (r = 0.76) between the plasma clearance and the blood: plasma ratio of tacrolimus because of the strong binding of tacrolimus to erythrocytes and its slow efflux into plasma.l 511 The binding of tacrolimus to erythClin. Pharmacokinet. 29 (6) 1995
Venkataramanan et al.
418
Table VII. Pharmacokinetics of tacrolimus (determined using enzyme-multiplied immunoassay) Patient population
No. of Biological Dose (mglkg) pts fluid [route]
t,;"z (h)
Vss (Ukg)
CL (Uh)
F(%)
tmax
Reference
(h)
Liver transplant
9
Plasma
0.15 [IV]
15.5 ± 11.2
17.9±9.8
105.6 ± 105.0
Liver transplant
3
Plasma
0.15 [IV]
3.5-40.5
5-56
25.2-366
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
30.1 ± 14.7
118.3±39.9
Blood
2.7-21.6mg [IV] 4-12mg[PO]
12.1 ±4.7
16
12.1 ±4.7
0.906±0.29 3.8± 1.2
Hepatic dysfunction
5
Plasma
0.15 [IV/PO]
38.5
High dose
17
Plasma
open stoma
2
closed stoma
3 12
59 27
1-4
25± 10
72
51
25± 10
51
195
36
0.5-2
0.4-1.3 [PO]
145.7±82.3
15
Plasma
0.15 [IV/PO]
53.2 - 222.6
5-10
2.8
Plasma
0.15 [IV/PO]
43
2.8
Blood
0.02 [IV] 0.08 [PO]
59 33
Small bowel transplant:
Kidney transplant
22±6.7
0.9 ± 0.21
2.8±0.9
12.1 ±4.2
Kidney transplant
15
Blood
0.02 [IV]
17.6
1.58 ± 0.45
6.8 ± 3.5
22.4 ± 14.2
Awaiting kidney transplant
6
Blood
0.02 [IV/PO]
32.5 ±8.3
1.24 ±0.26
2.4 ± 1.1
14.1 ± 12.4
1.5 ± 0.27
57 54 100
1.4 ± 0.6
42
Kidney transplant
7
Blood
0.02 [IV]
Kidney transplant
37
Plasma
0.15 [IV] 0.3 [PO]
6.86 ± 2.9
2.5± 2.4
102
Kidney transplant
37
Blood
0.15 [IV]
8.04 ±4.87
2.4 ± 1.9
102
21 ± 19
Healthy individuals
5
Plasma
43± 15
17±7
34± 11
Healthy individuals
5
Blood
32± 10
0.87 ±0.22
2 ± 0.45
101
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 appears to be a major factor accounting for the large interpatient variability in the pharmacokinetics of tacrolimus. Nonlinear erythrocyte binding and slow efflux of tacrolimus from erythrocytes complicate the pharmacokinetic interpretation of plasma concentration-time profiles for tacrolimus. The volume of distribution (V p) of tacrolimus based on the plasma concentration measurement is greater than 20 Llkg197,S1 I indicating extensive distribution of tacrolimus outside the plasma compartment. The extensive binding of tacrolimus into red blood cells, however, leads to a lower estimate of the volume of distribution (Vb) [approximately I Llkg) based on blood tacrolimus concentrations. There is a strong linear relationship (r = 0 .73) between Vp and the maximum blood: plasma concentration ratio, and a poor relationship (r = 0.3) between Vb and the maximum blood: plasma con© Adis International Limited. All rights reserved.
centration ratio, indicating the red blood cell binding to be a major factor in the interindividual differences in the volume of distribution of tacrolimus.l 511
4. Factors Affecting Tacrolimus Pharmacokinetics Some of the factors affecting the absorption and distribution of tacrolimus have been discussed in sections 3. 1 and 3.2. Paediatric patients require higher doses of tacroIimus on a mg/kg basis, compared with adults.l 99,I051 This appears to be a result of the higher clearance of tacrolimus in children l561 (Venkataraman et aI., unpublished observations). The bioavailability of tacrolimus in children appears to be similar to that observed in adults. Clin. Pharmac okinet. 29 (6) 1995
419
Tacrolimus Clinical Pharmacokinetics
Tacrolimus concentrations were elevated in patients with poor liver function compared with patients with near-normal liver function.[34.59] Tacrolimus has a longer disposition half-life and reduced clearance in patients with liver impairment compared with patients with normal hepatic functionJ59.97] This is consistent with the fact that tacrolimus is primarily metabolised before elimination from the body. The elevated concentrations of tacrolimus in patients with impaired liver function are associated with significant nephrotoxicity)124.125] Elevated concentrations of tacrolimus metabolites have been reported in patients with liver dysfunction, indicating impaired biliary secretion of these metabolites.[27] As expected, there was no significant correlation between serum creatinine levels and clearance of tacrolimus (r = 0.36).[42] Most patients achieve therapeutic tacrolimus concentrations with a dosage of 0.3 mg/kg/day or less. However, there is a small percentage of patients (3%) who require> 0.4 mg/kg/day to achieve this)33] This is predominantly the result of low bioavailability of tacrolimus and, to a minor extent, of the high clearance of tacrolimus. Poor bioavailability is observed in a greater percentage of nonCaucasians (Asians, Blacks, Hispanics) when compared with Caucasians, suggesting possible racial differences in tacrolimus pharmacokinetics (Venkataraman et aI., unpublished observations).
5. Drug Interactions Transplant recipients generally receive multiple drug therapy, which predisposes them to a number of potential drug-drug interactions (table IX). Aluminium hydroxide gel appears to physically adsorb tacrolimus in vitro)106] Other in vitro studies indicate that tacrolimus concentrations are significantly decreased in the presence of magnesium oxide[106] due to a pH-mediated degradation. Widely variable trough plasma tacrolimus concentrations were observed in patients taking sodium bicarbonate temporally close to tacrolimus administration. Coadministration of tacrolimus with sodium bicarbonate results in lower blood concentrations oftacrolimus (Venkataraman et aI., unpub© Adis
International Limited. All rights reserved.
Table VIII. Summary pharmacokinetics of tacrolimus Parameter
Absorption Absorption rate constant. ka (h- 1) Time to Cmax• tmax (h) Cmax at steady-state. Cssmax (~g/Umg dose) Bioavailability, F (%)
Distribution Blood/plasma ratio in transplant patients Percentage bound in normal plasma Percentage bound to human albumin (4 g/dl)
Range
Mean
0.14-8.0 0.5-6.0 0.1-0.8
4.5 2
4.0-93
25
4-114
15 77
69
Percentage bound to human cx1-acid glycoprotein:
83 mg/dl 160 mg/dl
67 91 24
Percentage associated with lipoprotein Volume of distribution, V (Ukg):
5.0-65 0.5-1.4
plasma blood
Elimination Percentage metabolised Urinary excretion of unchanged drug
30
>99 <1
(%)
Terminal disposition half-life (h) Total body clearance. CL: blood (Uh/kg) plasma (Uh/kg)
4.0-41
12
0.03-0.09 0.6-5.4
0.06 1.8
lished observations). Separation of the administration of these 2 agents by at least 2 hours, or the replacement of sodium bicarbonate by sodium citrate and citric acid, results in stable trough plasma tacrolimus concentrations in patients. It is recommended that magnesium oxide, sodium bicarbonate and aluminium hydroxide gel be administered to patients at least 2 hours apart from tacrolimus. Magnesium chloride, aluminium hydroxide powder, aluminium hydroxide dried gel or calcium carbonate do not appear to alter tacrolimus concentrations in simulated gastric fIuid.l 106] Coadministration of a low-fat diet appears to have minimal or no effect on the extent of tacrolimus bioavailability, but delays the time to reach maximum concentrations of tacrolimus[107] (VenClin. Pharmacokinet. 29 (6) 1995
Venkataramanan et al.
420
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 increase in blood concentrations in rats)
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 increase in blood concentrations in rats)
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 with moderate fat content significantly reduces the rate and extent of tacrolimus bioavailability (by approximately 30%) in transplant recipients.[IDO] It is important to be consistent in taking tacrolimus in relation to food intake. The effect of coadministration of tacrolimus with grapefruit juice, a component of which is known to inhibit intestinal CYP3A enzymes, is not presently known. Since tacrolimus appears to be metabolised primarily by CYP3A4, an enzyme known to metabolise cyclosporin, it is anticipated that drugs known to affect blood cyclosporin concentrations are also likely to affect tacrolimus blood concentrations in patients (table VIII). Administration of erythromycinJ 108] ciotrimazole,l'09] fluconazole,[J 10] danazol [I I II and chloramphenicol (Venkataraman et aI., unpublished observations) appear to increase the plasma or blood concentration of tacrolimus in transplant recipients. In rats, erythromycin, ketoconazole, fluconazole, itraconazole, diltiazem, © Adis International Limited. All rights reserved.
danazol, verapamil and cimetidine increase blood tacrolimus concentrations. [I 12] The metabolism of tacrolimus in vitro by dexamethasone-induced rat liver microsomes is inhibited by ketoconazole, itraconazole, fluconazole, SKF525A, debrisoquine, quinidine, norethindrone, erythromycin, lidocaine (lignocaine), danazol, veraparnil, nicardipine, nifedipine, diltiazem, midazolam, mephenytoin and dapsone.[94] Metabolism of tacrolimus in vitro by human liver microsomes is significantly inhibited (>20%) by diltiazem, erythromycin, fluconazole, nifedipine, nilvadipine, prednisolone, rifampicin (rifampin), cyclosporin, ethinylestradiol, amphotericin B, and mildly inhibited «20%) by enoxacin, lincomycin, ofloxacin and norethindrone)84] In rats, tacrolimus blood concentration is not significantly affected by carbamazepine, phenobarbital (phenobarbitone) and phenytoin pretreatment, but is decreased by rifampicin and dexamethasone pretreatment (Venkataraman et aI., unpublished observations). While the use of abovementioned drugs Clin. Pharmacokinet. 29 (6) 1995
421
Tacrolimus Clinical Pharmacokinetics
with tacrolimus is not contra-indicated, it is important to monitor tacrolimus blood concentrations while using agents that are known or expected to affect tacrolimus pharmacokinetics, so that alterations in tacrolimus dosage can be made, in order to minimise toxicity or to prevent graft rejection. Combined use of tacrolimus and cyclosporin results in synergistic immunosuppression and increased nephrotoxicity. In dogs, tacrolimus kinetics are not altered by coadministration of cyclosporin (Venkataraman et aI., unpublished observations). Short term administration of tacrolimus does not affect the systemic clearance of cyclosporin in humans,ll131 but studies in dogs suggest that tacrolimus increases cyclosporin bioavailability without altering its systemic clearance. [I 141 This is indicative of the possible inhibition of intestinal metabolism of cyclosporin by tacrolimus, similar to the mechanism that is reportedly responsible for the erythromycin-cyclosporin interaction. Tacrolimus is known to inhibit in vitro hepatic metabolism of cyclosporin and other drugs at concentrations well above those observed in patients,l1l5-121] It is unlikely that, at blood concentrations observed in transplant recipients, tacrolimus will significantly alter the hepatic drug-metabolising capacity of a patient. The effect of tacrolimus on prednisolone kinetics is not known, but a possible inhibition of prednisolone metabolism may explain the use of lower doses of corticosteroids in patients receiving tacrolimus therapy. It is interesting to note that, while long term intramuscular administration of tacrolimus increased the pentobarbital-induced sleeping time in rats,l122110w oral doses of tacrolimus did not alter the pentobarbitalinduced sleeping time. Tacrolimus also has a minimal effect on the biliary excretion of bromosulphthalein, consistent with a lack of hepatotoxicity in patients receiving tacrolimus therapy.
6. Treatment of Drug Toxicity/Overdose In vitro studies indicate that activated charcoal can completely adsorb tacrolimus from a solution (Venkataraman et aI., unpublished observations). Thus, administration of activated charcoal is likely © Adis International Limited. All rights reserved.
to be of some benefit in treating patients who take an oral overdose of tacrolimus. Tacrolimus is highly bound to red blood cells and plasma proteins (see section 3.2), and is not readily dialysable, so haemodialysis will be oflimited use in treating tacrolimus overdose. In 2 patients, it was possible to reduce tacrolimus concentrations in plasma by continuous ultrafiltration,l l23 1 which was possibly the result of physical adsorption of tacrolimus onto the device rather than actual filtration and removal of the drug. The potential benefit of continuous ultrafiltration in treating patients with tacrolimus overdose needs to be further evaluated. In I liver transplant recipient, it was possible to increase tacrolimus elimination by administration of rifampicin; however, this observation requires confirmation in further studies.
7. Therapeutic Monitoring of Tacrolimus 7.1 Rationale for Monitoring
Tacrolimus is a drug with a narrow therapeutic index. Although lower blood concentrations may precipitate a rejection episode, higher concentrations may lead to nephrotoxicity and/or neurotoxicity. There appears to be some relationship between tacrolimus concentration and toxicity in transplant patients. It has been shown that in patients in whom the perioperative graft dysfunction did not improve rapidly, plasma tacrolimus concentrations were significantly elevated; these patients had a higher rate of renal dysfunction, often requiring dialysis,l124,125,146] An analysis of the adverse effects of tacrolimus indicated that early onset of nephrotoxicity in several patients, when other nephrotoxic factors were excluded, was significantly associated with higher tacrolimus plasma concentrations (mean value 4.3 flglL) in comparison with those who did not exhibit any nephrotoxicity (mean value 2.3 flglL),l126 1 In 3 additional studies in liver transplant patients, elevated plasmalblood tacrolimus concentrations were associated with nephrotoxicity.l56,127-129] Clin. Pharmacokinet. 29 (6) 1995
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Venkataramanan et al.
It is believed that blood/plasma concentration measurement might help to minimise the incidence and severity of tacrolimus-related neurotoxicity and nephrotoxicity.l129-13l) In patients with hyperbilirubinaemia, plasma concentrations enabled differentiation between toxicity and rejection;(20) the trough blood concentration of tacrolimus has been reported to be significantly higher in patients with renal impairment than in those with acute rejection. A clear relationship between other adverse effects of tacrolimus (hypertension, hyperkalaemia, glucose intolerance) and drug concentrations has not yet been demonstrated. In the case of immunosuppressive drugs such as cyclosporin and tacrolimus, it is difficult to establish a concentration-response (graft failure) relationship, in view of the grave consequences of a lack of response (rejection) to the drug, the lack of a good specific response parameter that can be monitored, and because of the practice of using combination therapy with other immunosuppressive agents (such as corticosteroids and azathioprine). A comparison of tacrolimus plasma concentrations! 132.133) or blood concentrations! 133) in patients
•
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4.5
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1.0 0.5
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c
at the time of rejection with a group of patients who did not experience any rejection episodes indicated no significant differences. It is also interesting to note that early cellular rejection after liver transplantation correlated better with low concentrations of tacrolimus in hepatic tissue and not with plasma concentrations.l l34 ) A number of variables, such as the lise of other nephrotoxic drugs, use of other immunosuppressive drugs, potential differences in the binding of tacrolimus to blood proteins, clinical status of the patients and the immune sensitivity of a patient (extent of mismatch), may well contribute to the overall differences in the immunosuppression and toxic symptoms observed in patients. The pharmacokinetics of tacrolimus are highly variable between patients (fig. 2) and within individual patients over a period of time.!33,44-45,49,51,133] This is reflected in the wide range of oral dosages of tacrolimus (I to 44 mg/day) that are required to maintain trough plasma concentrations of 0.5 to 5 J.lglL (or to maintain trough blood concentrations of 5 to 20 J.lglL) in clinically stable liver and kidney transplant patients (fig. 7). Patients who were
• •
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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)
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Tacrolimus Clinical Pharmacokinetics
o Blood concentration of tacrolimus A Plasma concentration of tacrolimus • Total bilirubin
48
:J'
40 ~ (J)
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32
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16
~ 55
8
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13 10 Days post-transplant
16
19
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22
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 exhibited up to 60% variation in trough plasma concentrations and up to 50% variation in trough blood concentrations. [I33J Therapeutic monitoring of tacrolimus will help to optimise tacrolimus therapy in these patient populations. Figure 8 is an illustration of blood (MEIA) and plasma (ELISA) concentrations of tacrolimus and bilirubin concentrations in a liver transplant patient over time. Monitoring blood/plasma tacrolimus concentrations helps to ensure patient compliance with drug therapy. This is important, as transplant patients receive several drugs in the long term and may tend to become noncompliant with time. Tacrolimus monitoring may aid in differential diagnosis of graft rejection and organ toxicity, and minimise or avoid the consequences of drug interactions.
7.2 Trough Concentration Monitoring In liver, small-bowel and kidney transplant recipients, the trough plasma and blood concentrations of tacrolimus (measured 12 hours after an oral dose) and the AVC values for plasma and blood are highly correlated (r2 = 0.94 and 0.92, respectively;[135] r2 = 0.94 and 0.89, respectively[51] This indicates that trough plasma or blood tacrolimus © Adis International Limited. All rights reserved.
concentration is a good indicator of the total body exposure of tacrolimus.
7.3 Methods/Matrix for Monitoring Tacrolimus Therapeutic monitoring of tacrolimus has been discussed in several reviews.£3 2,49,I07,136] Tacrolimus concentrations can be measured in plasma and blood, although from a clinical perspective it is not clear at this time whether blood or plasma is better for measurement of tacrolimus concentrations. However, a recent consensus conference on therapeutic monitoring of immunosuppressive drugs has recommended the use of blood as the matrix for monitoring the concentration of tacrolimus[I04] for the following reasons: (i) blood concentrations are higher and tend to yield a lower coefficient of variation in the analytical methodology used compared with plasma sample measurements; (ii) the red blood cell uptake of tacrolimus is saturable and temperature-dependent, and necessitates plasma separation at 37°C; (iii) processing of blood samples to obtain plasma is laborious and time-consuming; (iv) haemolysis will artefactually increase plasma tacrolimus concentrations; elin. Pharmacokinet. 29 (6) 1995
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(v) availability of blood tacrolimus assays; (vi) in a group of clinically stable patients receiving a fixed dose of tacrolimus, the trough plasma concentrations appear to be more variable than the corresponding trough blood concentrations;11331 and (vii) there is apparently a better correlation between rejection episodes and adverse effects versus trough blood tacrolimus concentrations than with trough plasma tacrolimus concentrations. Tacrolimus concentration in plasma appears to be independent of the anticoagulant used for obtaining the blood samples (Venkataraman et aI., unpublished observations). While ethylenediamine tetraacetic acid (EDTA) is the preferred anticoagulant, its use must be avoided if bioassay is contemplated. Plasma can easily be frozen and repeatedly measured without loss of tacrolimus for several months. Preliminary results indicate that metabolites of tacrolimus have a lower immunosuppressive activity,140.86] but the toxicity of the metabolites is not known at this time. The data published to date are based on methods that use monoclonal antibody or the MEIA method. Though not ideal, MEIA appears to be the most suitable method at the present time for monitoring tacrolimus. It is clear from the literature that specific assay methods (HPLC, monoclonal radioimmunoassay) for routine monitoring of cyclosporin concentrations in patients are no better than nonspecific methods (fluorescent polarisation immunoassay TDX, polyclonal radioimmunoassay).f 137] 7.4 Frequency of Tacrolimus Monitoring
Given the mean disposition half-life of tacrolimus of around 10 hours, it is necessary to wait at least 36 hours (3.3 half-lives) to reach a steadystate tacrolimus concentration after initiation of therapy or after a change in the administration regimen of tacrolimus. Ideally, blood concentrations should be monitored on day 2 or 3 after starting the infusion, on average 3 to 7 times weekly during the first few weeks after transplantation, and less frequently thereafter. Special circumstances (changes © Adis International limited. All rights reserved.
in liver function, presence of adverse effects, use of drugs that may alter tacrolimus kinetics) may warrant more frequent monitoring.l I04 ] 7.5 Precautions
Tacrolimus tends to adsorb onto polyurethane and other plastic catheters.fs.138.139] Blood sampling via catheters through which tacrolimus is infused will artificially elevate tacrolimus concentrations, and this practice must be avoided at all costs. Capillary blood samples obtained from finger pricking give essentially the same results as the venous or the arterial blood sample, and can be used in patients with limited venous access.11391 As tacrolimus is stable in blood, samples can be shipped at ambient temperatures for analysis.
8. Dosage Regimen Design An analysis of plasma tacrolimus concentrations in renal transplant recipients and the inhibition of cell proliferation in mixed lymphocyte cultures by the corresponding plasma samples indicated 90% inhibition of lymphocytes at a plasma concentration of 0.8 J..lg/L (Venkataraman et aI., unpublished observations). In agreement with this observation, initially (in the majority of patients) the 12-hour trough plasma tacrolimus concentrations were maintained at 0.5 to 2 J..lg/L; currently, the 12-hour trough blood tacrolimus concentrations are maintained between 5 and 20 J..lg/L. 24-Hour trough concentrations are 33 to 50% lower than the corresponding 12-hour trough 1eve1s.f I04 ] Concentrations are maintained towards the higher end of the range during the immediate postoperative period, and towards the lower end subsequently. Based on the pharmacokinetic parameters estimated in the study of Jain et aI.,197] an intravenous dosage regimen of tacrolimus 0.027 mg/kg/day during the immediate postoperative period is expected to produce a minimum steady-state plasma concentration of 0.8 J..lglL. Assuming an oral bioavailability of 27%, the minimum oral dose of tacrolimus required to maintain a similar average plasma concentration is 0.1 mg/kg/day. These predictions agree well with the clinical practice of Clin. Pharmacokinet. 29 (6) 1995
Tacrolimus Clinical Pharmacokinetics
Table X. Summary of recommendation by the consensus conference on tacrolimus monitoringl1041 1.
Regular therapeutic monitoring is essential during therapy
2.
Target 12·hour trough blood concentrations are 5·20 ].Ig/ml early post-transplant. 24-hour trough concentrations are 33-50% lower
3.
Whole blood with EDTA is the preferred matrix
4.
Blood samples can be maintained for 1 week or shipped under ambient temperatures
5.
Trough blood concentration is the preferred sample for monitoring
6.
IncStar'" ELISA offers greater sensitivity and Abbott MEIA provides a faster turn around time
7.
Irnmunoassays are nonspecific; HPLC/MS assay is specific and may be used in certain cases
8.
Food decreases absorption; monitoring is important when drugs which alter cy1ochrorne P450 3A are added to or deleted from therapy
9.
Internal and external proficiency testing programrnes are important for assessing the laboratory performance
10. Monitoring should start on day 2 or 3, and be carried out 3to 7-times a week for the first 2 weeks, and then less often unless indicated otherwise Abbreviations: EDTA =ethylenediamine tetraacetic acid; ELISA = enzyme-linked immunosorbent assay; HPLC = high performance liquid chromatography; MEIA microparticulate enzyme immunoassay; MS mass spectrometry.
=
=
using 0.05 mg/kg/day as the dosage by intravenous infusion, and 0.1 to 0.3 mg/kg/day as the oral dosage. Given the average disposition half-life of about 8 to 12 hours, the drug is normally administered twice a day. In certain cases, an intravenous and oral pharmacokinetic study may be useful in identifying patients who absorb tacrolimus poorly from those who eliminate it very rapidly; the latter patients may benefit from administration 3 times daily, while patients with poor absorption may need higher doses on a twice-daily regimen. Dose adjustments of tacrolimus are based on: • the clinical status of the patient (whether a patient is rejecting an organ or has a drug-related toxicity) • the functional status of the liver (administration of a lower dose in the presence of liver dysfunction to minimise overexposure of the drug and resulting toxicity) • the response to a nephrotoxic event (dose reduction if the patient experiences nephrotoxicity) © Adis International Limited. All rights reserved.
425
• trough blood/plasma tacrolimus concentrations (very low blood concentrations of <5 J.1g/L lead to dose increase; high blood concentrations of > 20 J.1g/L lead to dose reduction). A user-friendly Intelligent Dosing System (IDS) for estimating the dose required to achieve a desired plasma tacrolimus concentration in liver and kidney transplant recipients and in patients with autoimmune disease has been developed and validated.1140-1431 For dose individualisation, the knowledge base is updated with patient-specific feedback including the current dose, drug concentrations and new target concentrations. Steinmuellerl1441 has reported a model for predicting the total daily dose and modifying the administration regimen of tacrolimus in patients. The presence of a strong correlation (r= 0.583) between erythromycin breath test (predictor ofCYP3A activity) and tacrolimus dose suggests possible application of this test in predicting tacrolimus dose requirements in patients.11451 The recommendations of the Consensus conference on tacrolimus monitoring are summarised in table X. While cyclosporin and tacrolimus share a number of similar kinetic properties, there are several differences between them (table Xl).
9. Conclusions Tacrolimus is a novel immunosuppressive drug with a large inter- and intraindividual variation in its pharmacokinetics, with variable rates and extents of absorption, variable extents of blood protein binding and variable rates of elimination). It is incompletely bioavailable after oral administration, is bound extensively to red blood cells (the binding being saturable), is primarily eliminated by hepatic metabolism and has a narrow therapeutic index. Tacrolimus is administered to patients whose clinical situation requires them to receive several other drugs. Monitoring of tacrolimus concentrations in blood or plasma will help to optimise tacrolimus therapy. Blood tacrolimus concentrations are normally maintained between 5 and 20 J.1g/L. Clin. Phormacokinet. 29 (6) 1995
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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
Highly metabolised cytochrome P450 3A hydroxylation, demethylation, minimal conjugation
Highly metabolised cytochrome P450 3A hydroxylation, demethylation, conjugation
! Elimination i Absorption
! !
Effects of renal disease
No change
No change
Effects of haemodialysis
No change in clearance
No change in clearance
parent drug
Very low in urine
Very low in urine
metabolites
Excreted primarily in bile
Excreted primarily in bile
parent drug
Most active
Most active
metabolites
A lot less active
Less active
Drug interaction profile
Blood concentrations increase with enzyme inhibition; blood concentrations decrease with enzyme induction
Blood concentrations increase with enzyme inhibition; blood concentrations decrease with enzyme induction
Therapeutic monitoring method
Blood MEIA
Blood monoclonal FPINHPLC
Metabolism: major enzyme pathways
Effects of liver disease: intravenously administered drug orally administered drug
Elimination Absorption
Excretion
Activity
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 microparticulate enzyme immunoassay.
= fluorescence polarimetry immunoassay/high performance liquid chromatography;
Currently, MEIA is the method of choice for therapeutic monitoring of tacrolimus in blood. However, it is desirable to develop a more sensitive and specific method for monitoring tacrolimus. Our knowledge of the pharmacokinetics of tacrolimus is incomplete at this time, primarily due to the lack of sensitive, specific and readily available analytical methods. © Adis International Limited. All rights reserved.
MEIA
=
The contribution of tacrolimus metabolites to the toxicity and immunosuppressive activity of tacrolimus also needs to be further evaluated.
Acknowledgements Work reported here is supported in part by USPHS grant AM 33475 and a grant from the University of Pittsburgh.
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Tacrolimus Clinical Pharmacokinetics
References I. Zeevi A, Duquesnoy R, Eiras G, et al. Immunosuppressive effect of FKS06 on in vitro lymphocyte alloactivation. Transplant Proc 1987; 19: 40-4 2. Starzl TE, Todo S, Fung J, et al. FK S06 for liver, kidney and pancreas transplantation. Lancet 1989; ii: 1000-4 3. Todo S, Fung J, Starzl TE, et al. Liver, kidney and thoracic organ transplantation under FKS06. Ann Surg 1990; 212: 29S-302 4. Honbo T, Kobayashi M, Hane K, et al. The oral dosage form of FK-S06. Transplant Proc 1987; 19 Suppl. 6: 17-22 S. Taormino D, Abdallah HY, Venkataramanan R, et al. Stability and sorption of FK S06 in S% dextrose injection and 0.9% sodium chloride injection in glass, polyvinyl chloride, and polyolefin containers. Am J Hosp Pharm 1992; 49 (I): 119-22 6. Croyle MA, Venkataramanan R, Burckart GJ, et al. Adsorption of pediatric intravenous doses of tacrolimus in S% dextrose 10 IV administration sets. Am J Health-Sysl Pharm 1995. In press 7. Ko S, Nakajima Y, Kanehiro H, et al. The pharmacokinetic benefits of newly developed Iiposome-incorporated FKS06. Transplantation 1994; S8: 1142-4 8. Ko S, Nakajima Y, Kanehiro H, et al. Significance of newly developed Iiposomal FK S06 in canine liver transplantation. Transplant Proc 1995; I: 3SI-3 9. Lee M, Straubinger RM , Jusko WJ. Physicochemical, pharmacokinetics and pharmacodynamic evaluation of liposomal tacrolimus (FKS06) in rats. Pharm Res 1995; 12: IOSS-9 10. Freeman DJ, Stawecki M, Howson B. Stability of FKS06 in whole blood samples. Ther Drug Monit 1995; 17: 266-7 II. Ingels SC, Koenig J, Scott MG. Stability of FKS06 (Tacrolimus) in whole blood specimens. Clin Chern 1995; 41: 1320-1 12. Tamura K, Kobayashi M, Hashimoto K, et al. A highly sensitive method to assay FKS06 levels in plasma. Transplant Proc 1987; 19 Suppl. 6: 23-9 13. Cadoff E, Venkataramanan R, Krajack A, et al. Assay of FK S06 in plasma. Transplant Proc 1990; 22: SO-I 14. Warty VS, Venkataramanan R, Zendehrough P, et al. Practical aspects of FKS06 analysis (Pittsburgh Experience). Transplant Proc 1991; 23: 2730-1 IS. Wallemacq PE, Firdaous I, Hassoun A. Improvement and assessment of enzyme-linked immunosorbent assay to detect low FKS06 concentration in plasma or whole blood within 6 hours. Clin Chern 1993; 39: 104S-9 16. Kobayashi M, Tamura K, Katayama N, et al. FK S06 assay past and present - characteristics of FK S06 ELISA. Transplant Proc 1991; 23: 272S-9 17. Jusko WJ, D' Ambrosio R. Monitoring FKS06 concentrations in plasma and whole blood. Transplant Proc 1991; 23: 2732-S 18. D'Ambrosio R, Girzaitis N, Jusko WJ. Validation and quality assurance program for monitoring tacrolimus (FK S06) concentrations in plasma and whole blood. Ther Drug Monit 1993; IS: 414-26 19. Warty V, Zuckerman S, Venkataramanan R, et al. Tacrolimus analysis: a comparison of different methods and matrices. Ther Drug Monit 1995; 17: IS9-67 20. Winkler M, Christians U, Stoll K, et al. Comparison of different assays for the quantitation of FK S06 levels in blood or plasma. Ther Drug Monit 1994; 16: 281-6 21. D'Ambrosio R, Girzaitis N, Jusko WJ. Multicenter comparison of tacrolimus (FK S06) whole blood concentrations as measured by the Abbott 1M, analyzer and enzyme immunoassay
© Adis International Limited. All rights reseNed.
22.
23.
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2S.
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3 \.
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40. Zeevi A, Venkataramanan R, Warty V, et al. In vitro assessment of FK 506 immunosuppressive activity in transplant patients. Transplant Proc 1991; 23: 2897-9 41. Zeevi A, Eiras G, Kaufman C, et al. Correlation between bioassayed plasma levels of FK506 and lymphocyte growth from liver transplant biopsies with histological evidence of rejection. Transplant Proc 1991; 23: 1406-8 42. Gruber SA, Hewitt JM, Sorenson AL, et al. Pharmacokinetics of FK506 after intravenous and oral administration in patients awaiting renal transplantation. J Clin Pharmacol 1994; 34: 859-64 43. Venkataramanan R, Jain A, Warty VS, et al. Pharmacokinetics of FK506 following oral administration: a comparison of FK 506 and cyc1osporine. Transplant Proc 1991; 23: 931-3 44. Venkataramanan R, Jain A, Warty VS, et al. Pharmacokinetics of FK 506 in transplant patients. Transplant Proc 1991; 23: 2736-40 45. Venkataramanan R, Jain A, Abu-Elmagd K, et al. Pharmacokinetics of FK506 in liver transplant patients [abstract]. Pharm Res 1991; 8: S313 46. Peters DH, Fitton A, Plosker GL, et al. Tacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation. Drugs 1993; 46: 746-94 47. Hooks MA. Tacrolimus, a new immunosuppressant - a review of the literature. Ann Pharmacother 1994; 28: 50 I-I 0 48. Steinmiiller DR. FK506 and organ transplantation. Austin (TX): Medical Intelligence Unit, RG Landers Co., 1994; I-III 49. Venkataramanan R, Warty VS. Pharmacokinetics and monitoring of FK506 [Tacrolimus1. In: Thompson AW, Starzl TE, editors. Immunosuppressive drugs. London: Arnold Publishers, 1994: 80-91 50. Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus: a new immunosuppressive agent. Am J Health-Syst Pharm 1995; 52: 1521-35 51. Jusko WJ, Piekoszewski W, Klintmalm GB, et a!. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther 1995; 57: 281-90 52. Bottiger Y, Rafael G, Brattsrom C, et al. Tacrolimus (FK506) kinetics in liver and kidney transplant recipients [abstract]. Ther Drug Monit 1995; 17: 416 53. Swaminathan A, Burckart G, Venkataramanan R. Uptake of FK506 by rat intestinal rings [abstract]. Pharm Res 1993; 10: S389 54. Lee C, Hewitt J, Aweeka F, et a!. Pharmacokinetics of tacrolimus (FK506) prior to kidney transplantation [abstract]. Clin Pharmacol Ther 1994; 53: 151 55. Aweeka FT, Benet LZ, Gambertoglio JG, et al. Comparative pharmacokinetics of orally (PO) and intravenously (IV) administered tacrolimus (FK506) in pre- and post-kidney transplant recipients [abstract]. Clin Pharmacol Ther 1993 Feb; 53: 151 56. Yasuhara M, Hashida T, Toraguchi M, et a!. Pharmacokinetics and pharmacodynamics ofFK506 in pediatric patients receiving living-related donor liver transplantations. Transplant Proc 1995; 27: 1108-10 57. Jain AB, Venkataramanan R, Todo S, et al. Intravenous, oral pharmacokinetics, and oral dosing of FK 506 in small bowel transplant patients. Transplant Proc 1992; 24: 1181-2 58. Iwasaki K, Shiraga T, Nagase K, et a!. Pharmacokinetic study ofFK506 in the rat. Transplant Proc 1991; 23: 2757-9 59. Jain AB, Venkataramanan R, Cadoff E, et a!. Effect of hepatic dysfunction on FK 506 pharmacokinetics and trough concentrations. Transplant Proc 1990; 22 Suppl. I: 57-9
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Correspondence and reprints: Prof. Raman Venkataramanan, Department of Pharmaceutical Sciences, 718 Salk Hall, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Clin. Phormocokinet. 29 (6) 1995
