Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK-453,061), in healthy adult subjects

摘要

Aims: To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors. Methods: Two open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400mg once daily) on the pharmacokinetics of lersivirine (250mg once daily). Subjects received ketoconazole 400mg once daily or placebo on days 1-2 and received lersivirine 250mg once daily and ketoconazole 400mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000mg once daily) on the PK of lersivirine (500mg once daily). On days 1-7, subjects received lersivirine 500mg once daily plus either VPA 1000mg or placebo. Results: Compared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24h)) and maximum plasma concentration (C max) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24h) by 25% (90% CI 16%, 35%), with little effect on C max (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study. Conclusions: Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated.