title: Pharmacokinetic drug-drug interaction between ethinyl estradiol and gestodene, administered as a transdermal fertility control patch, and two CYP3A4 inhibitors and a CYP3A4 substrate.
abstract: Pharmacokinetic (PK) interactions between the cytochrome P450 3A4 (CYP3A4) pathway and transdermally administered ethinyl estradiol (EE) and gestodene (GSD) were investigated. This paper reports the findings of three open-label, intra-individual, one-way crossover, Phase I trials. In two studies, women used a novel contraceptive patch for 3 weeks during two 4-week study periods; in the second period, the CYP3A4 inhibitors erythromycin (Study 1) or ketoconazole (Study 2) were administered concurrently. In a third study, women received single doses of the CYP3A4 model substrate midazolam, alone and after 3 weeks of concurrent patch application. In each period, the EE/GSD patch (delivering low EE and GSD doses resulting in the same systemic exposure as a combined oral contraceptive containing 0.02 mg EE and 0.06 mg GSD) was applied once weekly for 3 weeks, with one patch-free week. Erythromycin, ketoconazole, and midazolam were administered orally. Main outcome measures were area under the curves (AUCs) and maximum plasma concentration (C max) of EE, and total and unbound GSD (Studies 1 and 2). AUC and C max of midazolam (Study 3). Co-administration of CYP3A4 inhibitors did not affect EE metabolism, and had only weak effects on the PK of total and unbound GSD. The patch had no clinically relevant effect on metabolism of the CYP3A4 substrate midazolam.
authors.affiliation: , Pücklerstr. 4a, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Winkler
authors.affiliation: , Boulevard de Dixmude 40, Brussels, Belgium.
authors.forename: Mark
authors.initials: M
authors.lastname: Goldammer
authors.affiliation: , Bayer Pharma AG, Müllerstr. 178, S110, 02, 706, 13353, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: , Bayer Pharma AG, Müllerstr. 178, S110, 02, 706, 13353, Berlin, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Rohde
authors.affiliation: , Bayer Pharma AG, Müllerstr. 178, S110, 02, 706, 13353, Berlin, Germany. christian.zurth@bayer.com.
authors.forename: Christian
authors.initials: C
authors.lastname: Zurth
mesh_terms: D000328:Adult; D003280:Contraceptives, Oral, Synthetic / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004347:Drug Interactions / Q000502:physiology; D004997:Ethinyl Estradiol / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009652:Norpregnenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013379:Substrate Specificity; D057968:Transdermal Patch; D055815:Young Adult
chemical_list: D003280:Contraceptives, Oral, Synthetic; D065692:Cytochrome P-450 CYP3A Inhibitors; D009652:Norpregnenes; C033273:Gestodene; D004997:Ethinyl Estradiol; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Compliance; Ethinyl estradiol; Gestodene; Pharmacokinetic; Safety; Transdermal female contraceptive patch