Characterization of the Pharmacokinetics of Vilaprisan: Bioavailability, Excretion, Biotransformation, and Drug-Drug Interaction Potential
Marcus-Hillert Schultze-Mosgau, Joachim Höchel, Olaf Prien, Torsten Zimmermann, Ashley Brooks, Jim Bush, Antje Rottmann, Marcus-Hillert Schultze-Mosgau, Joachim Höchel, Olaf Prien, Torsten Zimmermann, Ashley Brooks, Jim Bush, Antje Rottmann
Abstract
Background and objectives: In-vitro data suggest that clearance of vilaprisan is mediated by cytochrome P450 3A4 (oxidation) and aldoketoreductases (reduction). To fully understand the elimination and biotransformation pathways of vilaprisan, a selective progesterone receptor modulator, and to quantify the impact of cytochrome P450 3A4 inhibition on the pharmacokinetics of vilaprisan, two clinical studies in healthy postmenopausal women were conducted.
Methods: In study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [14C]-labeled vilaprisan in six subjects. In study 2, pharmacokinetics were determined after single oral administration of 4 mg of vilaprisan without and with concomitant administration of the strong cytochrome P450 3A4 inhibitor itraconazole (200 mg/day) in 14 subjects. In addition, a microtracer dose of vilaprisan was given intravenously to determine absolute bioavailability, clearance, and volume of distribution.
Results: The dominant single compound in plasma was vilaprisan. No plasma metabolites exceeding 10% of total drug-related area under the concentration-time curve were detected. The absolute oral bioavailability of vilaprisan was ~ 60%. The mean clearance was ~ 7 L/h and the volume of distribution at steady state was ~ 360 L. Excretion occurred primarily via feces (73.5 ± 3.70% of dose; urine: 13.1 ± 1.71%; total recovery: 86.6 ± 2.81%), mostly in a metabolized form. Only small amounts of the parent drug were found in excreta. When vilaprisan was administered together with itraconazole, exposure to vilaprisan was increased 6.2-fold (90% confidence interval 5.4-7.2).
Conclusions: Vilaprisan is predominantly metabolized in the liver to a complex variety of metabolites, which are mainly excreted with feces. The pivotal role of cytochrome P450 3A4 in the metabolism of vilaprisan was confirmed.
Clinical trial registration: EudraCT numbers 2013-000707-16 (mass balance study) and 2014-004929-41 (drug-drug interaction/microtracer study); NCT02456129 (drug-drug interaction/microtracer study).
Conflict of interest statement
FundingThis study was sponsored by Bayer AG, Berlin, Germany. Medical writing support was provided by C. Hilka Wauschkuhn, Bonn and funded by Bayer AG.
Disclosure of potential conflicts of interestMarcus-Hillert Schultze-Mosgau, Joachim Höchel, Olaf Prien, Torsten Zimmermann, and Antje Rottmann are employees of Bayer AG. Ashley Brooks and Jim Bush have received consulting fees from Bayer AG.
Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consentInformed consent was obtained from all individual participants included in the studies.
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Source: PubMed