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

Abstract

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 loss-of-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.