Clinical and Genetic Determinants of Plasma Nevirapine Exposure Following an Intrapartum Dose to Prevent Mother-to-Child HIV Transmission

Abstract

Nevirapine is metabolized by cytochrome P450 (CYP) 2B6 and CYP3A4. We characterized relationships between clinical parameters, human genetics, pharmacokinetics, and human immunodeficiency virus type 1 (HIV-1) drug resistance mutations in pregnant women following single-dose intrapartum nevirapine. In AIDS Clinical Trials Group study A5207, women received nevirapine at onset of labor and were randomly assigned to receive lamivudine/zidovudine, emtricitabine/tenofovir, or lopinavir/ritonavir for 7 or 21 days. Plasma nevirapine level was quantified on postpartum day 1 and on weeks 1, 3, and 5. We assayed 214 polymorphisms in CYP2B6 and other genes and evaluated associations with pharmacokinetic parameters, including elimination constant, time to protein-adjusted 50% inhibitory concentration (IC50), and week 5 nevirapine level below the quantification limit. Among 301 women with evaluable pharmacokinetic and genotype data, lower body mass index and random assignment to receive lopinavir/ritonavir were associated with more rapid nevirapine elimination. Among those of African ancestry, longer time to IC50 was associated with CYP2B6 983T → C (P = .004) but not with CYP2B6 516G → T (P = .8). Among Indians, slower nevirapine elimination was associated with CYP2B6 516G → T (P = .04). Emergent resistance was infrequent and not associated with pharmacokinetics or CYP2B6 genotype. The effects on plasma drug exposure following single-dose nevirapine may be greater for CYP2B6 983T → C than for 516G → T and are less pronounced than at steady state.