Population pharmacogenetic‐based pharmacokinetic modeling of efavirenz, 7‐hydroxy‐ and 8‐hydroxyefavirenz
The Journal of Clinical Pharmacology(2014)
摘要
Objectives
The purpose of this study was to determine the demographic and pharmacogenetic covariates that influence the disposition of efavirenz (EFV) and its major metabolites. Methods: A population pharmacokinetic (PK) model was developed from a randomized, cross-over, drug-interaction study in healthy male Korean subjects (n=17). Plasma concentrations of EFV and its hydroxy-metabolites (0–120 hrs) were measured by LC/MS/MS. Genomic DNA was genotyped for variants in the cytochrome P450 (CYP) 2A6, 2B6, 3A5 and MDR1 genes. A PK model was built in a stepwise procedure using nonlinear mixed effect modeling in NONMEM 7. The covariate model was built using the generalized additive modeling and forward selection-backward elimination. Model-based simulations were performed to predict EFV steady-state concentrations following 200, 400, and 600 mg daily oral dose among different CYP2B6 genotypes
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