Premium
Effects of erythromycin at steady‐state concentrations on the pharmacokinetics of ulipristal acetate
Author(s) -
Pohl O.,
Osterloh I.,
Gotteland JP
Publication year - 2013
Publication title -
journal of clinical pharmacy and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.622
H-Index - 73
eISSN - 1365-2710
pISSN - 0269-4727
DOI - 10.1111/jcpt.12098
Subject(s) - ulipristal acetate , pharmacokinetics , steady state (chemistry) , erythromycin , pharmacology , chemistry , medicine , antibiotics , research methodology , biochemistry , population , environmental health , family planning
Summary What is known and objective 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 CYP 3A4 and to a small extent by CYP 1A2 and CYP 2D6. Erythromycin, a macrolide antibiotic, has been shown to be a moderate CYP 3A4 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 ( PGL 4002) were also evaluated. Methods 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. Results Geometric mean C max and AUC s 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 ): AUC 0–t 3·24 (2·75–3·83) and AUC 0–∞ (3·27 (2·79–3·83)], respectively, with no effect on median t max or t 1/2 . Geometric mean C max of PGL 4002 was decreased by 47% [geometric mean ratio point estimate (90% CI ): 0·523 (0·44–0·62)], but AUC s were increased by +62% and +66% [geometric mean ratio point estimates (90% CI ): AUC 0–t 1·62 (1·43–1·85) and AUC 0–∞ by 1·66 (1·47–1·88)], respectively, with no effect on median t max . However, geometric mean t 1/2 .doubled from 24 h to 48 h. No subject was discontinued from the study due to adverse events. What is new and conclusion Concomitant use of ulipristal acetate with erythromycin at therapeutic concentrations led to a limited increase in C max and a 3‐fold increase in AUC s for UPA and to a decrease in C max and an increase in AUC s and prolonged elimination for PGL 4002. This indicates that inhibition of CYP 3A4 impacted rate and extent of absorption of UPA and also its metabolism by slowing the elimination of its metabolite PGL 4002.