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

Abstract

Background and objectivesIn-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.MethodsIn 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.ResultsThe 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).ConclusionsVilaprisan 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 RegistrationEudraCT numbers 2013-000707-16 (mass balance study) and 2014-004929-41 (drug–drug interaction/microtracer study); NCT02456129 (drug–drug interaction/microtracer study).Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0607-4) contains supplementary material, which is available to authorized users.

Effect of hepatic impairment on the pharmacokinetics of vilaprisan: An open‐label, single‐dose, parallel‐group study

“…Of note, even in the cohort with moderate hepatic impairment, the increase in exposure was only mild (i.e. <1.75‐fold), indicating that the metabolic activity of CYP3A4, the main enzyme responsible for the clearance of vilaprisan, was only slightly reduced in this participant group. This could reliably be shown with vilaprisan where no compensating alternative elimination route such as involvement of extrahepatic eliminations is in place, for example renal excretion, which was marginal in all cohorts.…”

“…In this study, a single oral dose of vilaprisan 2 mg was well tolerated by participants of both sexes with mild or moderate hepatic impairment, and in participants with normal hepatic function. Safety findings in this study were comparable with observations from previous phase 1 and phase 2 studies in which vilaprisan was well tolerated, with no drug‐related serious AEs even at the maximal daily doses used in females . Here, the most frequently observed TEAEs were headache and nausea, which were also among the most common drug‐related AEs reported alongside ovarian and cervical cyst (identified at ultrasound), fatigue, abdominal or pelvic pain, other gastrointestinal disorders (flatulence, constipation), hot flushes, and dizziness in previous studies …”

“…Consistent with previous data, vilaprisan had only marginal renal excretion in all treatment groups . Geometric mean values of renal clearance up to 24 hours of 0.0684, 0.0671, 0.0443 and 0.0486 L h −1 were determined in mild hepatic impairment, moderate hepatic impairment, control mild hepatic impairment and control moderate hepatic impairment cohorts.…”

“…Clinical results from an intravenous microtracer study showed that vilaprisan is extensively distributed into tissues, as reflected by a large volume of distribution at steady state of ~360 L, and has a moderate plasma clearance of ~7 L/h with negligible contribution of renal clearance to total elimination. The terminal plasma elimination half‐life of ~40 hours is similar after intravenous and oral administration . In vitro interaction studies suggested no clinically relevant interaction of vilaprisan with the main CYP enzymes or transporters (i.e.…”

Discovery of Vilaprisan (BAY 1002670): A Highly Potent and Selective Progesterone Receptor Modulator Optimized for Gynecologic Therapies

“…In contrast, the unchanged parent compound vilaprisan (compound 18 ) was the main component in human plasma . Only a few minor metabolites formed by the reduction and oxidation of the steroid skeleton were identified in human plasma, each not exceeding 10 % of the AUC of total drug‐related compounds.…”