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

@entity5322 @entity1 @entity5396 @entity1140
PURPOSE: The once daily formulation of @entity1140 is an important immunosuppressive drug. Interpatient variability in metabolism has been related to genetic variation in @entity5322 and @entity5396 . However, in liver transplantation, both donor and recipient genotypes may affect pharmacokinetics. The primary objective of this study was to investigate the effect of @entity5322 *22 and @entity5396 *3 of both donor and recipient on once daily @entity1140 pharmacokinetics. The secondary objective was to develop a limited sampling model able to accurately predict exposure. METHODS: Stable liver transplant @entity1 receiving once daily @entity1140 (N  =  66) were included. Population pharmacokinetic analysis was performed with @entity1 of whom DNA was available (N  =  49), and demographic factors, @entity5322 *22 and @entity5396 *3, were tested as covariates. Moreover, a limited sampling model was developed using data of 66 @entity1 . RESULTS: Pharmacokinetics was best described by a two-compartment model with delayed absorption. @entity5396 *1 carrying recipients engrafted with a @entity5396 *1 carrying liver had an average 1.7-fold higher clearance compared to non-carriers. @entity5396 *1 carrying recipients engrafted with a @entity5396 *1 non-carrying liver or vice versa showed an average 1.3-fold higher clearance compared with non-carriers. @entity5322 *22 was not significantly associated with once daily @entity1140 pharmacokinetics. Using 0, 2, and 3  h postdose as limited sampling model resulted in significantly improved prediction of @entity1140 exposure compared with trough concentration. CONCLUSIONS: Both donor and recipient @entity5396 genotype significantly influences @entity1140 once daily pharmacokinetics. In contrast, @entity5322 *22 appears not suitable as biomarker. The developed limited sampling model can be used to accurately estimate @entity1140 once daily exposure.
