Clinical and genetic determinants of plasma nevirapine exposure following an intrapartum dose to prevent mother-to-child HIV transmission

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: CYP2B6; nevirapine; pharmacogenetics; pharmacokinetics; pregnancy.

Figure 1.

Plasma nevirapine concentration-time profiles following receipt of a single intrapartum 200-mg dose of nevirapine and relationship with body mass index (BMI). Top panels are scatter plots of measured plasma nevirapine concentrations around each time point at 1 day (±1 day), 7 days (±2 days), 21 days (±3 days), and 35 days (±3 days) after dose receipt. The x-axes represent days after dose. The y-axes represent plasma nevirapine concentrations (log₁₀ scale). Horizontal dotted lines indicate the 50% inhibitory concentration (IC₅₀) for nevirapine. Bottom panels represent relationships between BMI and time to reach nevirapine plasma IC₅₀. Left panels denote data for 217 women of African ancestry, and right panels denote data for 84 Indian women.

Figure 2.

Plasma nevirapine concentration-time profiles stratified by genotype following receipt of a single intrapartum 200-mg dose of nevirapine. Top panels denote data for 217 women of African ancestry, and bottom panels denote data for 84 Indian women. Left panels contain data stratified by CYP2B6 516G→T genotype, and right panels contain data stratified by CYP2B6 983T→C genotype. Mean nevirapine concentrations over time are connected by lines, and error bars represent SDs. The horizontal dotted line indicates the protein-adjusted 50% inhibitory concentration for nevirapine (46 ng/mL).