LAUSR

INTRODUCTION Meltdose tacrolimus (Envarsus®) is marketed as a formulation with a more consistent exposure. Due to the narrow therapeutic window, therapeutic drug monitoring is essential to maintain adequate exposure. The primary objective of this study was to develop a population pharmacokinetic (PK) model of Envarsus® among liver transplant patients and select a limited sampling strategy (LSS) for AUC estimation. The secondary objective was to investigate potential covariates including CYP3A/IL genotype suitable for initial dose optimization when converting to Envarsus®. METHODS Adult liver transplant patients were converted from prolonged release tacrolimus (Advagraf®) to Envarsus® and blood samples were obtained using whole blood and dried blood spot sampling. Subsequently the population PK parameters were estimated using non-linear-mixed effect modelling. Demographic factors, recipient and donor CYP3A4, CYP3A5, IL-6, -10 and -18 genotype were tested as potential covariates to explain inter-individual variability (IIV). RESULTS 55 patients were included. A two compartmental model with delayed absorption was the most suitable to describe population PK parameters. The population PK parameters were as follows: clearance: 3.27 L/h; intercompartmental clearance (Q): 9.6 L/h, volume of distribution of compartment 1 and 2: 95 L and 500 L respectively. No covariates were found to significantly decrease IIV. The best 3-point LSS was t=0,4,8 with a median bias of 1,8% (-12.5 - 12.5). CONCLUSION The LSS can be used to adequately predict the AUC. No clinically relevant covariates known to influence the PK of Envarsus®, including CYP3A status, were identified and therefore do not seem useful for initial dose optimization.