title: Pharmacokinetic and pharmacodynamic interactions between the hepatitis C virus protease inhibitor, boceprevir, and the oral contraceptive ethinyl estradiol/norethindrone.
abstract: OBJECTIVE
  The purpose of this study was to examine drug interactions between boceprevir, a hepatitis C virus NS3/4A protease inhibitor, and a combined oral contraceptive containing ethinyl estradiol (EE) and norethindrone (NE).
  
  
  METHODS
  A single-center, open-label study was conducted in 20 healthy female volunteers. In three consecutive 28-day treatment periods, subjects received EE/NE (0.035 mg/1 mg; 21 days on, 7 days off). During period 3, subjects also received boceprevir (800 mg three times daily) for 28 days.
  
  
  RESULTS
  Coadministration of boceprevir with EE/NE did not affect NE AUC0-24 but slightly reduced NE C max. Geometric mean ratios (GMRs) for NE AUC0-24 and C max with EE/NE alone and EE/NE plus boceprevir were 0.96 (90% confidence interval (CI), 0.87-1.06) and 0.83 (90% CI, 0.76-0.90). Coadministration of boceprevir with EE/NE reduced EE AUC0-24 and C max by 26 and 21%, with GMRs of 0.74 (90% CI, 0.68-0.80) and 0.79 (90% CI, 0.75-0.84). Boceprevir had no effect on mid-cycle luteinizing hormone (LH), follicle-stimulating hormone (FSH), or sex hormone-binding globulin levels, and progesterone concentrations remained <1 ng/ml during the luteal phase. Adverse events reported in this study were consistent with the well-established safety profile of boceprevir.
  
  
  CONCLUSIONS
  Serum progesterone, LH, and FSH levels indicate that ovulation was suppressed during coadministration of boceprevir with EE/NE. Coadministration of boceprevir with combined oral contraceptives containing EE and ≥1 mg of NE is therefore unlikely to alter contraceptive effectiveness. The ovulation suppression activity of oral contraceptives containing lower doses of NE, and of other forms of hormonal contraception during coadministration with boceprevir, has not been established.
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA.
authors.forename: Wen H
authors.initials: WH
authors.lastname: Lin
authors.forename: Hwa-Ping
authors.initials: HP
authors.lastname: Feng
authors.forename: Craig R
authors.initials: CR
authors.lastname: Shadle
authors.forename: Terry
authors.initials: T
authors.lastname: O'Reilly
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Joan R
authors.initials: JR
authors.lastname: Butterton
mesh_terms: D000293:Adolescent; D000328:Adult; D003277:Contraceptives, Oral, Combined / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004338:Drug Combinations; D004347:Drug Interactions; D004997:Ethinyl Estradiol / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D016174:Hepacivirus; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D009640:Norethindrone / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011374:Progesterone / Q000097:blood; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D012738:Sex Hormone-Binding Globulin / Q000032:analysis; D055815:Young Adult
chemical_list: D003277:Contraceptives, Oral, Combined; D004338:Drug Combinations; D011480:Protease Inhibitors; D012738:Sex Hormone-Binding Globulin; C020416:norethindrone acetate, ethinyl estradiol, ferrous fumarate drug combination; D004997:Ethinyl Estradiol; D011374:Progesterone; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D011392:Proline; D009640:Norethindrone