The development of a pharmacokinetic model describing the disposition of efavirenz and its two major metabolites; 8-hydroxyefavirenz and 8,14-dihydroxyefavirenz
Abstract
Efavirenz (EFV) is currently recommended by the international AIDS society as part of a combination regimen for the initial treatment of human immunodeficiency virus (HIV) infected patients. Efavirenz therapeutic response and toxicity are associated with high inter-individual variability. This variability could be attributed to variation of EFV pharmacokinetics (PK). Efavirenz is metabolized by the cytochrome P450 (CYP) metabolizing enzymes, primarily by the CYP2B6 isoenzyme. Inter-individual variability of CYP2B6 may partially explain the variability associated with EFV. The goal of this research direction was to develop a PK model to describe the disposition of EFV and its major metabolites that could be used to evaluate the impact of CYP2B6 genotype on the estimated PK parameters. Pharmacokinetic models were fit to plasma concentration-time data of EFV and its major metabolites using a standard two-stage approach and a one-stage analysis (non-linear mixed effect modeling). The initial parameters for the modeling procedure were estimated using compartmental and non-compartmental mathematical procedures. Model discrimination was based on diagnostic plots that included individual plasma concentrations versus time plots, predicted versus observed concentrations plots, and statistical analyses. One way analysis of variance (ANOVA) was used to compare the final model-estimated PK parameters between subjects with the wild type (*1/*1), *1/*6, and *6/*6 CYP2B6 genotype. Efavirenz disposition was characterized by a two-compartment model following first order absorption. Approximately 45% of EFV total clearance was through the metabolic formation of 8-hydroxyefavirenz (8-OH EFV). The disposition of 8-OH EFV was characterized by a two-compartment model. Further hydroxylation into 8,14-dihydroxyefavirenz (8,14-diOH EFV) accounted for approximately 95% of the 8-OH EFV total clearance. The disposition of 8,14-diOH EFV was characterized by one-compartment model. There was no statistically significant difference in the primary PK parameters of EFV or its major metabolites between the 3 CYP2B6 genotypes (*1/*1, *1/*6, and *6/*6) in this single dose study. This is the first pharmacokinetic model developed describing EFV and its major metabolites. This model may be utilized to assess the effect of CYP2B6 genotype and other sources of variability during steady state conditions. Ultimately, this may help guide the optimal dosing of EFV to achieve desired clinical outcomes.
Degree
M.S.
Advisors
Overholser, Purdue University.
Subject Area
Pharmacy sciences
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