Population Pharmacokinetic-Pharmacogenetic Study of Nevirapine in HIV-Infected Cambodian Patients

Abstract

The aims of this ANRS12154 open-label, single-center, multiple-dose pharmacokinetic study were to characterize nevirapine pharmacokinetics in a Cambodian population of HIV-infected patients and to identify environmental and genetic factors of variability, focusing on the CYP2B6, CYP3A5, and ABCB1 (MDR1) genes. A total of 170 Cambodian HIV-infected patients were included. Nevirapine trough concentrations were measured after 18 and 36 months of starting antiretroviral treatment and in samples drawn during a dosing interval in a subset of 10 patients. All data were analyzed by nonlinear mixed-effects modeling. The effect of covariates was investigated using the population pharmacokinetic model. Patients carrying homozygous lossof-function alleles CYP3A5 6986A>G, CYP2B6 516G>T, CYP2B6 1459C>T, and ABCB1 3435C>T represent 42.4%, 9.2%, 0%, and 18% of the population, respectively. The median nevirapine trough concentrations did not differ after 18 and 36 months of treatment (5,705 ng/ml [range, <50 to 13,871] and 5,709 ng/ml [range, <50 to 15,422], respectively). Interpatient and intrapatient variabilities of nevirapine apparent clearance were 28% and 17%, respectively. CYP2B6 516G>T and creatinine clearance were found to significantly affect nevirapine apparent clearance. The estimated nevirapine apparent clearances were 2.95 liters/h, 2.62 liters/h, and 1.86 liters/h for CYP2B6 516GG, CYP2B6 516GT, and CYP2B6 516TT genotypes, respectively. The impact of creatinine clearance was small. This study demonstrates that 95% of the patients had sustained nevirapine exposure well above the 3,000-ng/ml threshold. Nevirapine clearance was shown to be affected by CYP2B6 516G>T genetic polymorphism and creatinine clearance, although this explained only part of the interpatient variability, which remains low compared to that for other antiretroviral drugs.In resource-limited settings, nonnucleoside HIV-1 reverse transcriptase inhibitors (NNRTI) are the WHO-recommended backbone of first-line antiretroviral therapy. At the time of the study, nevirapine in combination with two nucleoside analog inhibitors of reverse transcriptase such as stavudine and zidovudine, in addition to lamivudine, was the recommended antiretroviral regimen in treatment-naïve patients, mainly because of the availability of WHO-prequalified low-cost generic fixed-dose combinations (7, 27). In Cambodia, the prevalence of HIV infection among the general population aged between 15 and 49 years peaked at 2% in 1998 and declined to 0.9% in 2006. This decrease has been attributed to many deaths among people infected during the early years of the epidemic before implementation of the continuum of care and the scaling-up of HIV prevention, care, and treatment programs. At the end of 2009, it is estimated that about 37,000 patients were on antiretroviral drug regimens and 69.5% were on a nevirapine backbone regimen (National Center for HIV/AIDS, Dermatology and STD [NCHADS]; http://www.nchads.org/). Therefore, worldwide, most patients living with AIDS who need antiretr...

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.…”

Co-infection tuberculose et VIH

“…Ces études ont exploré des aspects fondamentaux de la co-infection VIH-tuberculose : rôle des sous-populations lymphocytaires T et NK (natural killer) dans la physiopathologie et la prédiction du syndrome inflammatoire de reconstitution immunitaire (IRIS) tuberculeux (ANRS 12153 CAPRI NK [7] et ANRS 12164 CAPRI T), variabilité pharmacocinétique et polymorphisme des cytochromes P450 dans une population de patients cambodgiens infectés par le VIH et traités par névirapine ou efavirenz [8] (ANRS 12154 PECAN) et, enfin, diversité génétique de la tuberculose et impact sur la mortalité et l'expression clinique de la tuberculose (ANRS 12278).…”

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

“…Several studies have reported that the polymorphisms 516G>T and 983T>C in the CYP2B6 gene are associated with variations in NVP pharmacokinetics in ethnically diverse populations [32][33][34][35][36], although the clinical impact remains uncertain since an association between greater NVP exposure and toxic effects has not been fully demonstrated.…”