title: Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women.
abstract: BACKGROUND
  We evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E₂V) and dienogest (DNG).
  
  
  METHODS
  CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E₂V 2 mg/DNG 3 mg (days 1-17) and concomitant rifampicin (600 mg, days 12-16). Ratios of the area under the serum concentration-time curve between 0 and 24 h [AUC(0-24 h)] and maximum serum concentration (C(max)) of E₂ and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E₂V 2 mg/DNG 3 mg (days 1-14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8-14. Mean ratios of AUC(0-24 h) and C(max) of E₂ and DNG on days 7 and 14 are presented.
  
  
  RESULTS
  Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E₂C(max) and AUC(0-24 h) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E₂ of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean C(max) and AUC(0-24 h) of both E₂ and DNG. Geometric mean ratios of C(max) and AUC(0-24 h) for E₂ were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively.
  
  
  CONCLUSIONS
  Significant drug-drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E₂V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable.
authors.affiliation: Bayer HealthCare Pharmaceuticals, 13353 Berlin, Germany. hartmut.blode@bayer.com
authors.forename: Hartmut
authors.initials: H
authors.lastname: Blode
authors.forename: Susan
authors.initials: S
authors.lastname: Zeun
authors.forename: Susanne
authors.initials: S
authors.lastname: Parke
authors.forename: Torsten
authors.initials: T
authors.lastname: Zimmermann
authors.forename: Beate
authors.initials: B
authors.lastname: Rohde
authors.forename: Uwe
authors.initials: U
authors.lastname: Mellinger
authors.forename: Michael
authors.initials: M
authors.lastname: Kunz
mesh_terms: D000368:Aged; D000890:Anti-Infective Agents / Q000009:adverse effects*; D001711:Biotransformation / Q000187:drug effects; D003277:Contraceptives, Oral, Combined / Q000493:pharmacokinetics; D003278:Contraceptives, Oral, Hormonal / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis*; D004338:Drug Combinations; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004917:Erythromycin / Q000009:adverse effects*; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015914:Estrogen Replacement Therapy; D004970:Estrone / Q000031:analogs & derivatives / Q000097:blood; D005260:Female; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects*; D008875:Middle Aged; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D017698:Postmenopause; D012293:Rifampin / Q000009:adverse effects*
chemical_list: D000890:Anti-Infective Agents; D003277:Contraceptives, Oral, Combined; D003278:Contraceptives, Oral, Hormonal; D004338:Drug Combinations; C454300:estradiol valerate-dienogest; D004970:Estrone; D004958:Estradiol; D004917:Erythromycin; D009277:Nandrolone; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C017296:estrone sulfate; D007654:Ketoconazole; D012293:Rifampin