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Bootcongres

Fri, March 28th, 2014, 11:05 - 11:15

Population pharmacokinetics and pharmacogenetics of once daily tacrolimus formulation (advagraf®) in liver transplant patients.



D.J.A.R. Moes, S.A.S. Bent, J.J. Swen, T. van der Straaten, H.W. Verspaget, H-J. Guchelaar, J. den Hartigh, B. van Hoek

Moderator(s): H.J. Metselaar en M. Warlé

Location(s): Grote zaal

Category:

Background: The once daily formulation of tacrolimus is an important immunesuppressive drug metabolized by intestinal and hepatic CYP3A enzymes. Tacrolimus has a small therapeutic window and highly variable pharmacokinetics which make it difficult to maintain adequate exposure and prevent serious side effects. Inter-patient variability in tacrolimus metabolism has been related to both the CYP3A4 and CYP3A5 genotype. However, in liver transplants, both donor and recipient genotypes may affect pharmacokinetics. The aim of this study was to investigate the effect of CYP3A4*22 and CYP3A5*3 of both donor and recipient on once daily tacrolimus pharmacokinetics in liver transplant recipients and to develop a limited sampling model to accurately estimate tacrolimus once daily formulation exposure. Methods: Stable liver transplant patients receiving once daily tacrolimus (N=49) were included. Blood concentrations were determined with liquid chromatography tandem mass spectrometry (LCMS/MS). Population pharmacokinetic analysis was performed using NONMEM and demographic factors, CYP3A4*22 and CYP3A5*3 were tested as covariates. Moreover a limited sampling model was developed.

Results: Tacrolimus once daily formulation pharmacokinetics was best described by a two compartment disposition model with delayed absorption. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 carrying liver had a 1.65 fold higher clearance compared to non-carriers. CYP3A5*1 carrying recipients engrafted with a CYP3A5*1 non-carrying liver or vice versa showed a 1.13 fold higher clearance compared to non-carriers. CYP3A4*22 was not associated with once daily tacrolimus pharmacokinetics. A limited sampling model using 0, 1 and 3 hours postdose resulted in a significantly improved prediction of tacrolimus exposure.

Conclusions: Dose adjustments based on CYP3A5 genotypeof both donor and recipient are indicated. In contrast CYP3A4*22 appears not suitable as biomarker for tacrolimus pharmacokinetics. 0, 1 and 3 hours postdose as limited sampling model can be used to accurately estimate tacrolimus once daily formulation exposure in liver transplantation.