Ulipristal acetate - safety and pharmacokinetics following multiple doses of 10-50 mg per day

Abstract

Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for benign gynaecological conditions such as uterine myoma. The safety and pharmacokinetics of multiple-dose UPA and its N-mono-demethylated metabolite, PGL4002, were investigated in women. The double-blind, placebo-controlled study randomized 32 healthy women of reproductive age to receive 10 consecutive daily doses of placebo, 10, 20 or 50mg UPA. Safety assessments included vital signs, physical examination, ECG, clinical laboratory tests and reporting of adverse events. Blood samples for pharmacokinetic analysis were collected on Days 1 and 10 at intervals until 168h after multiple dosing. UPA was well tolerated at all doses. Mild or moderate adverse events occurred with similar frequency in UPA and placebo groups. UPA median tmax was 0·75 and 0·89h, and mean plasma half-life was between 38 and 49h. Cmax values (Day 1) were 42·2, 130·9 and 354·8ng/mL for the UPA 10, 20 and 50mg treatment groups, respectively. Corresponding Cmax values for Day 10 were 63·7, 169·8 and 454·9ng/mL. AUCSS values on Day 10 were 216·6, 602·8 and 1655·7ngh/mL after 10, 20 and 50mg UPA, respectively. For the principal metabolite PGL4002, tmax and plasma elimination half-life values were similar to those of UPA. PGL4002 AUCSS Day 10 values were 84·7, 203·6 and 452·1ngh/mL for 10, 20 and 50mg groups, respectively. Daily administration of UPA at therapeutic and supratherapeutic doses was well tolerated by women of reproductive age. UPA exposure increases with dose. Exposure to PGL4002 is approximately one-third that of UPA.