Population pharmacokinetics and genetics of oral meltdose tacrolimus (Envarsus) in stable adult liver transplant recipients.
Br J Clin Pharmacol
; 87(11): 4262-4272, 2021 11.
Article
em En
| MEDLINE
| ID: mdl-33786892
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transplante de Fígado
/
Tacrolimo
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Humans
Idioma:
En
Revista:
Br J Clin Pharmacol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Holanda