The aims of this 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.
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 ten patients. All data were analyzed by nonlinear mixed effect modelling. The effect of covariates was investigated using the population pharmacokinetic model.
Patients carrying homozygous loss of function alleles of 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 (5705 (≤50 – 13871) ng/mL and 5709 (≤50 – 15422) ng/mL 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. Estimated nevirapine apparent clearance was 2.95 L/h, 2.62 L/h and 1.86 L/h for CYP2B6 516GG, 516GT and 516TT genotype, respectively. Impact of creatinine clearance is small.
This study demonstrates that 95% of the patients had a sustained nevirapine exposure well above the 3000 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 other antiretroviral drugs.