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.
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Notes
This patch was approved in various countries outside of the EU after this date.
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Acknowledgments
Dr Winkler is a former employee of Bayer Technology Services GmbH, and Dr Ludwig, Dr Rohde, and Dr Zurth are employees of Bayer Pharma AG. Mark Goldammer is a former employee of PHC Pharma Consult, affiliated to Bayer Pharma AG. Financial support for this study was provided by Bayer Pharma AG, Berlin, Germany. Editorial assistance was provided by Ogilvy 4D, Oxford, UK, funded by Bayer Pharma AG.
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Winkler, J., Goldammer, M., Ludwig, M. et al. Pharmacokinetic drug–drug interaction between ethinyl estradiol and gestodene, administered as a transdermal fertility control patch, and two CYP3A4 inhibitors and a CYP3A4 substrate. Eur J Drug Metab Pharmacokinet 40, 389–399 (2015). https://doi.org/10.1007/s13318-014-0215-8
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DOI: https://doi.org/10.1007/s13318-014-0215-8