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 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.

FIG. 1.

Plasma nevirapine concentrations versus time in 170 Cambodian HIV patients at M18 and M36 (a) and in the extensive pharmacokinetic substudy (b). Values below the LOQ are represented by the asterisk at 0 on the y axis.

FIG. 2.

Nevirapine concentrations versus time overlaid to the 90th interval and the median predicted from the final model (a to c) and normalized prediction discrepancies versus time (d to f) at all evaluations sorted by genotype for the CYP2B6 516G>T polymorphism.

FIG. 3.

(a) Mean over the individual nevirapine clearance at the different occasions (M18, M36, and the extensive pharmacokinetic substudy) for each of the 152 patients with an informed CYP2B6 516G>T genotype, sorted by genotype with the corresponding median (on a log scale). (b) Individual nevirapine clearance estimated at each occasion plotted versus the corresponding creatinine clearance observation. Data from each patient are connected by a segment. The solid line represents a regression spline (with y and x axes on a logarithmic scale). Patients with genotypes GG, GT, and TT for the CYP2B6 516G>T polymorphism are represented with the symbols +, × and ⋄, respectively.