Associations betweenCYP2B6Polymorphisms and Pharmacokinetics after a Single Dose of Nevirapine or Efavirenz in African Americans

Abstract

Background Polymorphisms in CYP2B6 affect steady-state plasma concentrations of nevirapine and efavirenz. In many resource-limited countries, single-dose nevirapine has been widely prescribed to pregnant women at delivery to reduce mother-to-child transmission. We characterized relationships between genetic polymorphisms and the pharmacokinetics of single doses of nevirapine and efavirenz. Methods Plasma drug concentrations were determined over 13 days following a 200-mg oral dose of nevirapine administered to non-pregnant, HIV-negative African Americans. A 600-mg oral dose of efavirenz was subsequently administered and pharmacokinetic sampling repeated. Pharmacokinetic parameters were estimated using a non-compartmental approach. Primary analyses involved two CYP2B6 polymorphisms (516G>T and 983T>C) known to predict increased steady-state plasma nevirapine and efavirenz exposure. Exploratory analyses involved another 51 polymorphisms in CYP2B6, ABCB1, CYP3A4 and CYP3A5. Results Based on composite CYP2B6 516/983 genotype, the 34 participants comprised 10 extensive, 17 intermediate, and 7 slow metabolizer genotypes. Composite CYP2B6 516/983 genotype was significantly associated with plasma drug exposure and clearance for efavirenz but not for nevirapine. Exploratory analyses suggested possible associations between additional CYP2B6 polymorphisms and pharmacokinetics for nevirapine and efavirenz. Conclusions Selective pressure for drug-resistant HIV-1 following single-dose nevirapine may not differ substantially by CYP2B6 516/983 genotype. Additional polymorphisms, genes and populations warrant further study.

Presence of Lamivudine or Emtricitabine Is Associated with Reduced Emergence of Nonnucleoside Reverse Transcriptase Inhibitor Mutations in an Efavirenz-Based Intermittent Antiretroviral Treatment Regimen

“…Halflives were highly variable (21,22), and as expected, they were shorter than the half-life reported after administration of a single dose (6), as a consequence of the autoinduction property of efavirenz. A genetic polymorphism of CYP2B6 G516T (4,6,10,14,16,17,20,23) leads to prolonged efavirenz half-lives and has been recognized as a factor that may explain the variability of efavirenz pharmacokinetics (5,21). Unfortunately, at the time the study was designed, blood samples were not collected for pharmacogenetics, and the ethnicity of patients was not recorded.…”

Pharmacokinetics of Phase I Nevirapine Metabolites following a Single Dose and at Steady State

“…Data and specimens for these pharmacokinetic analyses were from individuals who had participated in two previously published studies (17,18). This analysis was approved by the Na-tional Ethics Committee of Cambodia and by the Vanderbilt University Institutional Review Board.…”

“…This analysis was approved by the Na-tional Ethics Committee of Cambodia and by the Vanderbilt University Institutional Review Board. Plasma samples were from 10 healthy, HIVnegative African Americans (group A) who had received a single 200-mg oral dose of nevirapine (17) and from 10 HIV-infected Cambodians (group B) from the ESTHER (Ensemble pour une Solidarité Thérapeu-tique en Réseau) at the Calmette Hospital (Phnom Penh, Cambodia) (18). In both groups, plasma was kept frozen until analysis, and genotype data for CYP2B6 *1*6 were available from the previous studies (17,18).…”

“…Plasma nevirapine assays for group A were performed in the United States (17), and those for group B were performed in Cambodia (18), both by liquid chromatography according to previously validated assays. The lower limit of quantification was 50 ng/ml.…”

Simultaneous quantification of zidovudine, stavudine, lamivudine and nevirapine by Micellar Electrokinetic Capillary Chromatography

“…Compliance testing and therapeutic drug monitoring would therefore be beneficial to preserve the limited availability of second line treatment options in these countries [5]. It is notable that some variants of the cytochrome P450 CYP2B6 gene, known to predict decreased plasma NVP or EFV clearance, are more frequent in black African individuals [6][7][8][9]. It is therefore crucial to develop affordable ARV quantification methods to allow intensive pharmacokinetic studies in these populations.…”