Laboratoire Rodolphe Mérieux de Phnom Penh

Pharmacokinetics of phase I nevirapine metabolites following a single dose and at steady state

Fan-Havard P, Liu Z, Chou M, Ling Y, Barrail-Tran A, Haas DW, Taburet AM; the ANRS12154 study group

Antimicrob. Agents Chemother. AAC.02294-12; published ahead of print 4 March 2013


Nevirapine is one of the most extensively prescribed antiretrovirals worldwide. The present analyses used data and specimens from two prior studies to characterize and compare plasma nevirapine phase I metabolite profiles following a single 200 mg oral dose of nevirapine in 10 HIV-negative African Americans, and at steady state with 200 mg twice-daily in 10 HIV-infected Cambodians. Nevirapine was assayed by HPLC. The 2-, 3-, 8- and 12-hydroxy and 4-carboxy metabolites of nevirapine were assayed by LC/MS/MS. Pharmacokinetic parameters were calculated by non-compartmental analysis. The metabolic index for each metabolite was defined as the ratio of metabolite AUC to nevirapine AUC. Every metabolite concentration was much less than the corresponding nevirapine concentration. The predominant metabolite after single dose and at steady state was 12-hydroxynevirapine. From single to steady state, the metabolic index increased for 3-hydroxynevirapine (p<0.01), but decreased for 2-hydroxynevirapine (p<0.001). The 3-hydroxynevirapine metabolic index was correlated with nevirapine apparent clearance (p<0.001). These findings are consistent with induction of CYP2B6 (3-hydroxy metabolite) and a possible inhibition of CYP3A (3-hydroxy metabolite), although these are preliminary data. There were no such changes in metabolic indexes for 12-hydroxynevirapine or 4-carboxynevirapine. Two subjects with the CYP2B6 *6*6 genetic polymorphism had metabolic indexes in the same range as other subjects. These results suggest that nevirapine metabolite profiles change over time under the influence of enzyme induction, enzyme inhibition, and host genetics. Further work is warranted to elucidate nevirapine biotransformation pathways, and implications for drug efficacy and toxicity.

Keywords: Nevirapine, genetic polymorphism

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