title: The effect of lersivirine, a next-generation NNRTI, on the pharmacokinetics of midazolam and oral contraceptives in healthy subjects.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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 %.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pfizer Global Research and Development, Sandwich, UK.
authors.forename: John
authors.initials: J
authors.lastname: Davis
authors.forename: Grant
authors.initials: G
authors.lastname: Langdon
authors.forename: Gary
authors.initials: G
authors.lastname: Layton
authors.forename: Chew Lan
authors.initials: CL
authors.lastname: Chong
authors.forename: Marie-Noella
authors.initials: MN
authors.lastname: Ndongo
authors.forename: Manoli
authors.initials: M
authors.lastname: Vourvahis
mesh_terms: D000293:Adolescent; D000328:Adult; D001711:Biotransformation / Q000187:drug effects; D003276:Contraceptives, Oral / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D016912:Levonorgestrel / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D009570:Nitriles / Q000009:adverse effects / Q000494:pharmacology*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D003276:Contraceptives, Oral; D004338:Drug Combinations; D009570:Nitriles; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; C531151:UK 453,061; C072593:ethinyl estradiol, levonorgestrel drug combination; D004997:Ethinyl Estradiol; D016912:Levonorgestrel; D008874:Midazolam