Characterization of the Pharmacokinetics of Vilaprisan: Bioavailability, Excretion, Biotransformation, and Drug-Drug Interaction Potential

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

Funding

This 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 interest

Marcus-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 approval

All 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 consent

Informed consent was obtained from all individual participants included in the studies.

Figures

Fig. 1

Geometric mean vilaprisan (VPR) and [14C]-radioactivity concentrations in plasma following a single oral dose of 5 mg [14C]VPR (mass balance study). Geometric means ± geometric standard deviations (calculated if two thirds or more of the individual values were above the lower limit of quantitation, 0.1 µg/L), n = 6. Plasma samples beyond 168 h were not further investigated as the overall content of total radioactivity was too low

Fig. 2

Cumulative recovery of total [14C]-radioactivity in excreta following a single oral dose of [14C]vilaprisan 5 mg (mass balance study). Mean ± standard deviation (SD); n = 6

Fig. 3

Representative radio-chromatograms (mass balance study)

Fig. 4

Proposed main metabolic pathways of vilaprisan in humans. AKR aldoketoreductase, CYP cytochrome P450, VPR vilaprisan

Fig. 5

Metabolites in excreta [% of dose] and contributions of metabolic pathways to overall excretion (mean of six subjects). VPR vilaprisan

Fig. 6

Geometric mean concentrations of vilaprisan (± standard deviations) (VPR) and [14C]VPR in plasma after single oral and intravenous (i.v.) administration of VPR 4 mg (drug–drug interaction/microtracer study). All 14 subjects received a single oral dose of VPR 4 mg as a tablet and seven of these subjects additionally received a single i.v. dose of [14C]VPR 15.7 µg (37 KBq) [30-min infusion, 1 mL/min] starting 1.5–2 h after administration of the oral dose, i.e., around the time of the expected maximum plasma concentration of the oral dose

Fig. 7

Geometric mean concentrations of vilaprisan (VPR) in plasma after single oral administration of VPR 4 mg with and without concomitant administration of itraconazole (ITZ) 200 mg/day (drug–drug interaction/microtracer study). Geometric means ± geometric standard deviations [calculated if two thirds or more of the individual values were above the lower limit of quantitation (LLOQ), 0.1 µg/L]; n = 14

Fig. 8

Exposure to vilaprisan after single oral administration of vilaprisan 4 mg with and without concomitant administration of itraconazole (ITZ) 200 mg/day (drug–drug interaction study). Left hand graph: box: 25th–75th percentile. Horizontal line: median. Vertical lines extend from the box as far as the data extend to a maximum distance of 1.5 interquartile ranges; any value more extreme is plotted separately. Right hand graph: time course of individual area under the concentration–time curve from time zero to time t (AUC0–11d) values; n = 14

Fig. 9

Concentrations of vilaprisan metabolite M-4 (BAY 1139463) in pooled plasma after single oral administration of vilaprisan 4 mg with and without concomitant administration of itraconazole (ITZ) 200 mg/day (drug–drug interaction study). M-4 concentrations in plasma were below the lower limit of quantitation after 12 h after administration of vilaprisan without concomitant administration of ITZ

Fig. 10

Structure of vilaprisan in comparison to mifepristone and ulipristal acetate