The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects
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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.
- The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects
European Journal of Clinical Pharmacology
Volume 68, Issue 11 , pp 1567-1572
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- Oral contraceptives
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- Author Affiliations
- 1. Pfizer Global Research and Development, Sandwich, UK
- 5. Genentech Inc, San Francisco, CA, USA
- 6. PTx Solutions Ltd, 45 Queen Street, Deal, UK
- 2. Pfizer Clinical Research Unit, Raffles Hospital, Singapore, Singapore
- 7. Lilly-NUS Centre for Clinical Pharmacology Pte Ltd, 10 Medical Drive S, Singapore, Singapore
- 3. Pfizer Research Clinic, CHU Erasme/ULB University, Anderlecht, Brussels, Belgium
- 4. Pfizer Global Research and Development, 219 East 42nd Street, New York, NY, 10017, USA