Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients

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Abstract

Purpose

The once daily formulation of tacrolimus is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in CYP3A4 and CYP3A5. However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of CYP3A4* 22 and CYP3A5* 3 of both donor and recipient on once daily tacrolimus pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure.

Methods

Stable liver transplant patients receiving once daily tacrolimus ( N = 66) were included. Population pharmacokinetic analysis was performed with patients of whom DNA was available ( N = 49), and demographic factors, CYP3A4* 22 and CYP3A5* 3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 patients.

Results

Pharmacokinetics was best described by a two-compartment model with delayed absorption. CYP3A5* 1 carrying recipients engrafted with a CYP3A5* 1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. CYP3A5* 1 carrying recipients engrafted with a CYP3A5* 1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. CYP3A4* 22 was not significantly associated with once daily tacrolimus pharmacokinetics. Using 0, 2, and 3 h postdose as limited sampling model resulted in significantly improved prediction of tacrolimus exposure compared with trough concentration.

Conclusions

Both donor and recipient CYP3A5 genotype significantly influences tacrolimus once daily pharmacokinetics. In contrast, CYP3A4* 22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate tacrolimus once daily exposure.

Electronic supplementary material

The online version of this article (doi:10.1007/s00228-015-1963-3) contains supplementary material, which is available to authorized users.

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Most cited references 32

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Some suggestions for measuring predictive performance.

L Sheiner, Deryk S. Beal (1981)

The performance of a prediction or measurement model is often evaluated by computing the correlation coefficient and/or the regression of predictions on true (reference) values. These provide, however, only a poor description of predictive performance. The mean square prediction error (precision) and the mean prediction error (bias) provide better descriptions of predictive performance. These quantities are easily computed, and can be used to compare prediction methods to absolute standards or to one another. The measures, however, are unreliable when the reference method is imprecise. The use of these measures is discussed and illustrated.

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Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM.

Ron J. Keizer, Michel van Benten, Jos H. Beijnen … (2011)

Pharmacokinetic-pharmacodynamic modeling using non-linear mixed effects modeling (NONMEM) is a powerful yet challenging technique, as the software is generally accessed from the command line. A graphical user interface, Piraña, was developed that offers a complete modeling environment for NONMEM, enabling both novice and advanced users to increase efficiency of their workflow. Piraña provides features for the management and creation of model files, the overview of modeling results, creation of run reports and handling of datasets and output tables, and the running of custom R scripts on model output. Through the secure shell (SSH) protocol, Piraña can also be used to connect to Linux clusters (SGE, MOSIX) for distribution of workload. Modeling with NONMEM is computationally burdensome, which may be alleviated by distributing runs to computer clusters. A solution to this problem is offered here, called PCluster. This platform is easy to set up, runs in standard network environments, and can be extended with additional nodes if needed. The cluster supports the modeling toolkit Perl speaks NONMEM (PsN), and can include dedicated or non-dedicated PCs. A daemon script, written in Perl, was designed to run in the background on each node in the cluster, and to manage job distribution. The PCluster can be accessed from Piraña, and both software products have extensively been tested on a large academic network. The software is available under an open-source license. 2011 Elsevier Ireland Ltd. All rights reserved.

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A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients.

Laure Elens, Keith C. Heyde, Vincent Haufroid … (2011)

Tacrolimus (Tac) is a potent immunosuppressant with considerable toxicity. Tac pharmacokinetics varies between individuals and thus complicates its use in preventing rejection after kidney transplantation. This variability might be caused by genetic polymorphisms in metabolizing enzymes. We used TaqMan analyses to evaluate the impact of a newly discovered CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) single-nucleotide polymorphism (SNP) (rs35599367C>T; CYP3A4*22) on Tac pharmacokinetics in 185 renal transplant recipients who participated in an international randomized controlled clinical trial (fixed-dose, concentration-controlled study). The overall mean daily-dose requirement to reach the same predose Tac blood concentration was 33% lower for carriers of the T variant allele than for rs35599367CC patients (95% CI, -46% to -20%; P = 0.018). When combined with the *3 genotype of the CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) gene, the rs35599367C>T SNP was also associated with a risk of supratherapeutic Tac concentrations (>15 μg/L) during the first 3 days after surgery, with an odds ratio of 8.7 for carriers of the CYP3A4 T allele plus CYP3A5*3/*3 (P = 0.027) and 4.2 for the CYP3A4 CC homozygotes plus CYP3A5*3/*3 (P = 0.002), compared with CYP3A4 CC homozygotes having 1 or 2 CYP3A5*1 alleles. The overall increase in the Tac dose-adjusted trough blood concentration was +179% for carriers of the CYP3A4 T allele with CYP3A5*3/*3 (P T polymorphism is associated with a significantly altered Tac metabolism and therefore increases the risk of supratherapeutic Tac concentrations early after transplantation. Analysis of this CYP3A4*22 SNP may help in identifying patients at risk of Tac overexposure.

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Author and article information

Contributors

D. J. A. R Moes: +31 71 526 2790 , d.j.a.r.moes@lumc.nl

Journal

Journal ID (nlm-ta): Eur J Clin Pharmacol

Journal ID (iso-abbrev): Eur. J. Clin. Pharmacol

Title: European Journal of Clinical Pharmacology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0031-6970

ISSN (Electronic): 1432-1041

Publication date (Electronic): 31 October 2015

Publication date PMC-release: 31 October 2015

Publication date (Print): 2016

Volume: 72

Pages: 163-174

Affiliations

[ ]Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands

[ ]Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands

[ ]Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands

Article

Publisher ID: 1963

DOI: 10.1007/s00228-015-1963-3

PMC ID: 4713720

PubMed ID: 26521259

SO-VID: 5c11576a-353f-4323-b68b-e44acbc2faad

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 24 April 2015

Date accepted : 5 October 2015

Custom metadata

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: once daily tacrolimus,advagraf,population pharmacokinetics,pharmacogenetics,liver transplantation

Data availability:

ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine

Keywords: once daily tacrolimus, advagraf, population pharmacokinetics, pharmacogenetics, liver transplantation

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation in stable liver transplant recipients

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Abstract

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Methods

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Electronic supplementary material

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Dermal Microdialysis in Pharmacokinetics

Most cited references 32

Some suggestions for measuring predictive performance.

Piraña and PCluster: a modeling environment and cluster infrastructure for NONMEM.

A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients.

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