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

Academic Article

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 (IC 50), 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. © The Author 2013.
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    Author List

  • Vardhanabhuti S; Acosta EP; Ribaudo HJ; Severe P; Lalloo U; Kumarasamy N; Taulo F; Kabanda J; Oneko O; Ive P
  • Start Page

  • 662
  • End Page

  • 671
  • Volume

  • 208
  • Issue

  • 4