title: Absence of effect of oral rifaximin on the pharmacokinetics of ethinyl estradiol/norgestimate in healthy females.
abstract: BACKGROUND
  Rifaximin is an oral rifampin analog, and its activity is targeted within the gastrointestinal tract. Some analogs induce the cytochrome P450 family of oxidative enzymes. Ethinyl estradiol (EE), commonly found in oral contraceptives (OCs), is a known CYP3A4 substrate.
  
  
  OBJECTIVE
  To determine the potential effect of rifaximin on EE and norgestimate pharmacokinetics.
  
  
  METHODS
  In an open-label, crossover study, healthy females received a single dose of OC (EE 0.07 mg/norgestimate 0.50 mg). Following a 1 week washout period, individuals received rifaximin 200 mg every 8 hours for 3 days, with a single dose of OC administered with the ninth rifaximin dose. During both treatment periods, blood samples were collected periodically for up to 96 hours after each OC dose. Plasma concentration-time profiles and pharmacokinetic parameters were characterized for EE and 2 major metabolites of norgestimate, norgestrel (NG) and 17-deacetyl norgestimate (17-DNGM). A drug-drug interaction was confirmed if the 90% CI for the 2 treatment period comparison was outside the 80-125% limit.
  
  
  RESULTS
  Twenty-six of 28 women completed the study. No differences in pharmacokinetic parameters were observed for EE, NG, or 17-DNGM when a single dose of the OC was administered alone or with rifaximin. In addition, the 90% CI for the bioavailability contrasts (OC alone vs OC with rifaximin) for the maximum plasma concentration, area under the plasma concentration-time curve from zero to the last measurable plasma concentration or to infinity for EE, NG, and 17-DNGM all ranged from 86-118%. These intervals were within the predefined range for equivalence; therefore, no interaction was observed between OC and rifaximin. Rifaximin was well tolerated.
  
  
  CONCLUSIONS
  Administration of a 3 day dosing regimen of oral rifaximin was well tolerated and did not alter the pharmacokinetics of a commonly used combination OC containing EE and norgestimate.
authors.affiliation: Clinical Research and Development, ICON Development Solutions, Ellicott City, MD, USA.
authors.forename: Carol Braun
authors.initials: CB
authors.lastname: Trapnell
authors.forename: Margaret
authors.initials: M
authors.lastname: Connolly
authors.forename: Helen
authors.initials: H
authors.lastname: Pentikis
authors.forename: William P
authors.initials: WP
authors.lastname: Forbes
authors.forename: Doug K
authors.initials: DK
authors.lastname: Bettenhausen
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D003277:Contraceptives, Oral, Combined / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009644:Norgestrel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D012294:Rifamycins / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D000078262:Rifaximin; D013810:Therapeutic Equivalency
chemical_list: D000900:Anti-Bacterial Agents; D003277:Contraceptives, Oral, Combined; D012294:Rifamycins; D009644:Norgestrel; D004997:Ethinyl Estradiol; D003577:Cytochrome P-450 Enzyme System; C017576:norgestimate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000078262:Rifaximin