Pharmacokinetics and safety of the selective progesterone receptor modulator vilaprisan in healthy postmenopausal women

Objectives: Vilaprisan is a novel, potent, and highly selective progesterone receptor modulator, which might offer a promising option for the treatment of uterine fibroids. Methods and materials: In this randomized, placebo-controlled, parallel-group phase 1 study, the pharmacokinetics and safety of vilaprisan were investigated in healthy postmenopausal women. Subjects received a single oral dose of vilaprisan (1, 5, 15, or 30 mg) or placebo and - after a wash-out period - daily doses of the same strength over 28 days. Safety assessments included vital signs, ECGs, clinical laboratory tests, and adverse events. Blood samples for pharmacokinetic (PK) profiles were collected over 14 days after single dose (sd) and multiple dose (md; day 28). Results: Vilaprisan was well tolerated. Mild to moderate adverse events occurred with similar frequency at all dose levels. Following single dose, maximum vilaprisan concentrations were observed 1 - 2 hours post-dose. Terminal half-lives ranged from 31 to 38 hours. Maximum concentrations of vilaprisan (Cmax) and exposure to vilaprisan (AUC) increased roughly dose-proportionally from 3.74 mu g/L (1 mg) to 68.6 mu g/L (30 mg) and 58.5 mu gxh/L to 1,590 mu gxh/L, respectively. With daily dosing, accumulation consistent with the long terminal half-life was observed (AUC(0-24)(md)/AUC(0-24)(sd) ratios: 1.9 to 3.2). The ratio AUC(0-24)(md)/AUC(sd) increased with dose from similar to 1 (1 mg) to 1.5 (30 mg). Conclusions: Expdsure to vilaprisan increased roughly dose-proportionally in the dose range studied and accumulated after multiple dosing as expected based on t(1/2), indicating linear pharmacokinetics of vilaprisan in the expected therapeutic dose range.