The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects
Lersivirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile that exhibits potent antiretroviral activity against wild-type human immunodeficiency virus and clinically relevant NNRTI-resistant strains. Results from in vitro and in vivo investigations suggest that lersivirine is a cytochrome P450 (CYP3A4) inducer that is metabolized by CYP3A4 and uridine diphosphate glucuronosyltransferase (UGT) 2B7. In order to formally assess the effects of lersivirine on CYP3A4 metabolism and/or glucuronidation, we performed studies aimed at investigating the effects of lersivirine co-administration on the pharmacokinetics (PK) of midazolam, ethinylestradiol and levonorgestrel.
Two drug–drug interaction studies were performed. Healthy subjects were co-administered (1) single dose midazolam, a prototypical CYP3A4 substrate, followed by 14 days of lersivirine twice daily with single dose midazolam on the final day of lersivirine dosing or (2) 10 days of once-daily (QD) lersivirine and QD oral contraceptives (OCs; ethinylestradiol and levonorgestrel), substrates for CYP3A4, UGT2B7, and/or P-glycoprotein. The effects of co-administration on the PK parameters of midazolam and OCs were assessed.
At clinically relevant lersivirine doses (500–1,000 mg total daily dose), the mean plasma exposure of midazolam was reduced in a dose-dependent manner by 20–36 %. Co-administration of lersivirine 1,000 mg QD with OCs had minor PK effects, increasing ethinylestradiol exposure by 10 % and reducing levonorgestrel exposure by 13 %.
These data further support previous observations that lersivirine is a weak CYP3A4 inducer, a weak inhibitor of glucuronidation, and a P-glycoprotein inhibitor. In both studies, lersivirine appeared to have a good safety and tolerability profile.
KeywordsLersivirine UK-453,061 Pharmacokinetics Midazolam Oral contraceptives
Both studies (A5271005 and A5271007) were funded by Pfizer Inc. Editorial support was provided by Dr Bethan Hahn at Complete Medical Communications and was funded by ViiV Healthcare.
Conflict of interest
Manoli Vourvahis, Gary Layton and Marie-Noella Ndongo are all employees of and hold stock options in Pfizer Inc. John Davis, Grant Langdon and Chew Lan Chong were employees of and held stock options in Pfizer Inc. when the studies were performed. Both studies (A5271005 and A5271007) were funded by Pfizer Inc. Lersivirine is under development by Pfizer Inc. and ViiV Healthcare.
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