Different Nevirapine Metabolite Profiles with Single-dose and at Steady-state
P Fan-Havard1, Z Liu2, M Chou3, Y Lin2, A Barrail-Tran4,5, D Haas6, Anne-Marie Taburet*5, and ANRS 12154 Study Group
1Univ at Buffalo Sch of Pharmacy and Pharmaceutical Sci, Amherst, NY, US; 2Ohio State Univ Coll of Pharmacy, Columbus, US; 3Univ of Hlth Sci Faculty of Pharmacy, Phnom Penh, Cambodia; 4Univ Paris-Sud Faculty of Pharmacy, Chatenay-Malbry, France; 5BicÍtre Hosp Univ Paris-Sud, Le Kremlin-BicÍtre, France; and 6Vanderbilt Univ Sch of Med, Nashville, TN, US
Background: Nevirapine (NVP) undergoes phase 1 hydroxylation by CYP isoforms (2-OH by CYP3A4/5; 3-OH by CYP2B6; 8-OH by CYP2D6; and 12-OH by CYP3A4/5 and CYP2D6), with subsequent 4-carboxylation. It has been suggested that metabolites may mediate NVP toxicity. The purpose of this study was to characterize NVP metabolite profiles following a single-dose (SD) and at steady-state (SS) in cohorts from 2 previous studies.
Methods: †The SD cohort comprised 10 HIVĖ African Americans, a single 200-mg NVP dose, and serial plasma pharmacokinetic sampling for 13 days. The SS cohort comprised 10 HIV+ Cambodians, chronic twice-daily NVP 200-mg dosing, and serial plasma pharmacokinetic sampling for 12 hours. Parent NVP was assayed by HPLC, and 2-OH, 3-OH, 8-OH, 12-OH, and 4-carboxylation metabolites by LC/MS/MS. Pharmacokinetic parameters were calculated by non-compartmental analysis. With SD, AUC was extrapolated to infinity; with SS, AUC was calculated for 12 hours. Apparent NVP clearance (Cl/F) was dose divided by AUC. Metabolic index (MI) was defined as metabolite-to-NVP AUC ratio. Results are expressed as median and range.
Results: The SD and SS cohort, respectively, included 8 and 5 females, median ages were 25 and 32 years, and median weights were 68 and 52 kg. NVP Cl/F with SD and SS were 0.29 and 0.83 mL/min/kg, respectively (p<0.001). Parent NVP exceeded metabolite concentrations at every time point. Metabolite concentrations tended to parallel declines in NVP concentrations. With both SD and SS the major metabolite was 12-OH-NVP. Only with SS was 8OH-NVP detected. The Table shows MI values. A lower MI for 2-OH-NVP with SS suggests inhibition of CYP3A. The higher MI for 3-OH-NVP with SS is consistent with NVP induction of CYP2B6. There were no such changes in MI for 12-OH-NVP or 4-CA-NVP, which are formed in part by non-inducible CYP2D6.
Conclusions: †These data suggest that NVP metabolite profiles evolve over time as a consequence of CYP2B6 induction, and possibly CYP3A inhibition as demonstrated in vitro. We suspect that human genetic variants also play a role. These results may have implications for NVP toxicity and/or efficacy.