Effects of erythromycin at steady-state concentrations on the pharmacokinetics of ulipristal acetate

Abstract

Ulipristal acetate (UPA) is a novel selective progesterone receptor modulator for the treatment of benign gynaecological conditions such as uterine myoma. In vitro, it is mainly metabolized by the cytochrome P450 isoenzyme CYP3A4 and to a small extent by CYP1A2 and CYP2D6. Erythromycin, a macrolide antibiotic, has been shown to be a moderate CYP3A4 inhibitor. Thus, the aim of this study was to determine the effects of erythromycin at steady-state concentrations on the pharmacokinetics of UPA. Effects on the pharmacokinetics of the mono-demethylated metabolite of UPA (PGL4002) were also evaluated. This was a non-randomized, single-sequence, two-period, open, single-dose study in 18 healthy female subjects. Subjects received oral UPA (20 mg) once daily on days 1 and 13 and twice-daily erythromycin propionate administrations (500 mg) from days 9 through 17. Geometric mean Cmax and AUCs of UPA were increased by 24% [geometric mean ratio point estimate (90% CI): 1·24 (1·01-1·52)] and +224% and +227% [geometric mean ratio point estimates (90% CI): AUC0-t 3·24 (2·75-3·83) and AUC0-∞ (3·27 (2·79-3·83)], respectively, with no effect on median tmax or t1/2. Geometric mean Cmax of PGL4002 was decreased by 47% [geometric mean ratio point estimate (90% CI): 0·523 (0·44-0·62)], but AUCs were increased by +62% and +66% [geometric mean ratio point estimates (90% CI): AUC0-t 1·62 (1·43-1·85) and AUC0-∞ by 1·66 (1·47-1·88)], respectively, with no effect on median tmax. However, geometric mean t1/2.doubled from 24 h to 48 h. No subject was discontinued from the study due to adverse events. Concomitant use of ulipristal acetate with erythromycin at therapeutic concentrations led to a limited increase in Cmax and a 3-fold increase in AUCs for UPA and to a decrease in Cmax and an increase in AUCs and prolonged elimination for PGL4002. This indicates that inhibition of CYP3A4 impacted rate and extent of absorption of UPA and also its metabolism by slowing the elimination of its metabolite PGL4002.