title: 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.
authors.affiliation: Statistical Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts, USA.
authors.forename: Saran
authors.initials: S
authors.lastname: Vardhanabhuti
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Ribaudo
authors.forename: Patrice
authors.initials: P
authors.lastname: Severe
authors.forename: Umesh
authors.initials: U
authors.lastname: Lalloo
authors.forename: Nagalingeshwaran
authors.initials: N
authors.lastname: Kumarasamy
authors.forename: Frank
authors.initials: F
authors.lastname: Taulo
authors.forename: Joseph
authors.initials: J
authors.lastname: Kabanda
authors.forename: Olola
authors.initials: O
authors.lastname: Oneko
authors.forename: Prudence
authors.initials: P
authors.lastname: Ive
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sambarey
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Chan
authors.forename: Jane
authors.initials: J
authors.lastname: Hitti
authors.forename: Francis
authors.initials: F
authors.lastname: Hong
authors.forename: Deborah
authors.initials: D
authors.lastname: McMahon
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D018890:Chemoprevention / Q000379:methods; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D015658:HIV Infections / Q000517:prevention & control*; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control*; D020128:Inhibitory Concentration 50; D008297:Male; D008657:Metabolic Clearance Rate; D019829:Nevirapine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D010949:Plasma / Q000737:chemistry; D011110:Polymorphism, Genetic; D011247:Pregnancy; D013997:Time Factors; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating
keywords: CYP2B6; nevirapine; pharmacogenetics; pharmacokinetics; pregnancy