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

Abstract

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

Tacrolimus Updated Guidelines through popPK Modeling: How to Benefit More from CYP3A Pre-emptive Genotyping Prior to Kidney Transplantation

“…Contrasting with these observations, a number of previous studies have failed to highlight the benefit of introducing CYP3A4 ∗ 22 in modeling Tac inter-individual variability through popPK-approaches, with a few exceptions (Shi et al, 2011; Zuo et al, 2013; Zhang et al, 2015; Moes et al, 2016; Andreu et al, 2017). This is not surprising as the majority of studies were performed in Asian populations where CYP3A4 ∗ 22 is absent, as it is for individuals of African origins.…”

“…However, to our knowledge, only two PopPK studies have examined the combined effects of the CYP3A4 ∗ 22 and CYP3A5 ∗ 3 SNPs, showing that CYP3A4 DOF can exacerbate the CYP3A5 LOF (Moes et al, 2016; Andreu et al, 2017). The definition of a rationale categorization of the patient into poor (PM), intermediate (IM), and extensive metabolizer (EM) according to these two SNPs has been successfully proposed previously and takes the advantage of being clearly understandable for clinicians and medical staff.…”

Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach

“…A population PK approach to evaluate the limited sampling strategy may be another method to estimate midazolam AUC. This approach has been used to estimate immunosuppressant drug exposures in transplant patients and in a phenotyping cocktail study . The traditional, noncompartmental analysis, limited sampling strategy for model development is the use of stepwise, linear regression .…”

Tacrolimus Population Pharmacokinetics and Multiple CYP3A5 Genotypes in Black and White Renal Transplant Recipients

“…in other study populations that primarily enrolled white patients. 37,[43][44][45][46] In these analyses, CYP3A5*1 expressers exhibited a 1.2-to 2.3-fold increase in tacrolimus clearance compared to CYP3A5 non-expressers. 26 Significant differences among the 3 CYP3A5*3 genotype groups were found in 2 studies involving Korean adult 35 and Mexican pediatric renal transplant patients.…”

“…Unlike our analysis, the majority of the studies exploring the CYP3A5*3 variant show differences in tacrolimus clearance between CYP3A5 non‐expressers (*3/*3) or poor metabolizers in comparison to CYP3A5*1 expressers, which combine both intermediate (*1/*3) and extensive (*1/*1) metabolizers. These findings may be explained by the limited incidence of *1/*1 variant in other study populations that primarily enrolled white patients . In these analyses, CYP3A5*1 expressers exhibited a 1.2‐ to 2.3‐fold increase in tacrolimus clearance compared to CYP3A5 non‐expressers .…”