European Journal of Clinical Pharmacology

, Volume 68, Issue 11, pp 1567–1572

The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects

  • John Davis
  • Grant Langdon
  • Gary Layton
  • Chew Lan Chong
  • Marie-Noella Ndongo
  • Manoli Vourvahis
Short Communication



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.


Lersivirine UK-453,061 Pharmacokinetics Midazolam Oral contraceptives 

Supplementary material

228_2012_1287_MOESM1_ESM.doc (120 kb)
ESM 1(DOC 120 kb)

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • John Davis
    • 1
    • 5
  • Grant Langdon
    • 1
    • 6
  • Gary Layton
    • 1
  • Chew Lan Chong
    • 2
    • 7
  • Marie-Noella Ndongo
    • 3
  • Manoli Vourvahis
    • 4
  1. 1.Pfizer Global Research and DevelopmentSandwichUK
  2. 2.Pfizer Clinical Research UnitRaffles HospitalSingaporeSingapore
  3. 3.Pfizer Research ClinicAnderlecht, BrusselsBelgium
  4. 4.Pfizer Global Research and DevelopmentNew YorkUSA
  5. 5.Genentech IncSan FranciscoUSA
  6. 6.PTx Solutions LtdDealUK
  7. 7.Lilly-NUS Centre for Clinical Pharmacology Pte LtdSingaporeSingapore

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