Population pharmacokinetics and genetics of oral meltdose tacrolimus (Envarsus) in stable adult liver transplant recipients.

Autor: Martial LC; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, Netherlands., Biewenga M; Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, Netherlands., Ruijter BN; Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, Netherlands., Keizer R; InsightRX, San Francisco, CA, USA., Swen JJ; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, Netherlands., van Hoek B; Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, Netherlands., Moes DJAR; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, Netherlands.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2021 Nov; Vol. 87 (11), pp. 4262-4272. Date of Electronic Publication: 2021 May 04.
DOI: 10.1111/bcp.14842
Abstrakt: Aims: 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 nonlinear-mixed effect modelling. Demographic factors, and recipient and donor CYP3A4, CYP3A5, IL-6, -10 and -18 genotype were tested as potential covariates to explain interindividual variability.
Results: Fifty-five patients were included. A 2-compartment 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, 9.6 L/h; volume of distribution of compartments 1 and 2, 95 and 500 L, respectively. No covariates were found to significantly decrease interindividual variability. The best 3-point LSS was t = 0,4,8 with a median bias of 1.8% (-12.5-12.5).
Conclusions: 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.
(© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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