title: Effect of 7 days of phenytoin on the pharmacokinetics of and the development of resistance to single-dose nevirapine for perinatal HIV prevention: a randomized pilot trial.
abstract: OBJECTIVE
  To confirm whether 7 days of phenytoin, an enzyme inducer, would decrease the elimination half-life of single-dose nevirapine and to investigate its effect on the development of nevirapine resistance in pregnant, HIV-infected women.
  
  
  METHODS
  In a pharmacokinetic pilot trial (NCT01187719), HIV-infected, antiretroviral (ARV)-naive pregnant women ≥18 years old from Zambia and Tanzania and with CD4 cell counts >350 cells/mm(3) were randomized 1 : 1 to a control (zidovudine pre-delivery, single-dose nevirapine/zidovudine/lamivudine at delivery and zidovudine/lamivudine for 7 days post-delivery) or an intervention (control plus 184 mg of phenytoin once daily for 7 days post-delivery) group. Primary endpoints were the pharmacokinetics of and resistance to nevirapine.
  
  
  RESULTS
  Thirty-five and 37 women were allocated to the control and intervention groups, with median (IQR) ages of 27 (23-31) and 27 (23-33) years, respectively. Twenty-three and 23 women had detectable nevirapine levels at delivery and subsequent samples in the control and the intervention groups, respectively. Geometric mean (GM) (95% CI) plasma levels of nevirapine at delivery were 1.02 (0.58-1.78) mg/L and 1.14 (0.70-1.86) mg/L in the control and intervention groups, respectively (P = 0.76). One week after delivery, 0/23 (0%) and 15/22 (68%) control and intervention mothers, respectively, had undetectable levels of nevirapine (<0.05 mg/L; P<0.001). One week later, the figures were 10/21 (48%) and 18/19 (95%) mothers, respectively (P = 0.002). The GM (95% CI) half-life of nevirapine was 63.2 (52.8-75.7) versus 25.5 (21.6-30.1) h in the control group versus the intervention group (P < 0.001). New nevirapine mutations were found in 0/20 (0%) intervention-group mothers versus 1/21 (5%) control-group mothers. Overall, there was no difference in adverse events reported between the control and intervention arms (P > 0.28).
  
  
  CONCLUSIONS
  Adding 7 days of an enzyme inducer to single-dose nevirapine to prevent mother-to-child transmission of HIV significantly reduced subtherapeutic nevirapine levels by shortening the half-life of nevirapine. As prolonged subtherapeutic nevirapine dosage leads to the emergence of resistance, single-dose nevirapine could be used with phenytoin as an alternative if other ARVs were unavailable.
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Quirine
authors.initials: Q
authors.lastname: Fillekes
authors.forename: Eva P
authors.initials: EP
authors.lastname: Muro
authors.forename: Catherine
authors.initials: C
authors.lastname: Chunda
authors.forename: Susan
authors.initials: S
authors.lastname: Aitken
authors.forename: Elton R
authors.initials: ER
authors.lastname: Kisanga
authors.forename: Chipepo
authors.initials: C
authors.lastname: Kankasa
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Thomason
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D000927:Anticonvulsants / Q000008:administration & dosage*; D004347:Drug Interactions; D024882:Drug Resistance, Viral; D005260:Female; D006678:HIV / Q000187:drug effects* / Q000302:isolation & purification; D015658:HIV Infections / Q000517:prevention & control* / Q000635:transmission; D006207:Half-Life; D006801:Humans; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D019829:Nevirapine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010672:Phenytoin / Q000008:administration & dosage*; D010865:Pilot Projects; D011247:Pregnancy; D013636:Tanzania; D055815:Young Adult; D015024:Zambia
chemical_list: D019380:Anti-HIV Agents; D000927:Anticonvulsants; D010672:Phenytoin; D019829:Nevirapine
keywords: Africa; PK; nevirapine; prevention of mother-to-child transmission of HIV