Pharmacokinetic and Pharmacodynamic Profiles of Ethinylestradiol/Norgestimate Combination or Norethindrone upon Coadministration with Elagolix 150 mg Once Daily in Healthy Premenopausal Women

Abstract

Background: Two pharmacokinetic/pharmacodynamic studies were conducted to evaluate the potential drug-drug interaction between elagolix, an oral gonadotropin-releasing hormone receptor antagonist, and an oral contraceptive (ethinylestradiol [EE] 0.035 mg and norgestimate 0.18/0.215/0.25 mg) or progestin-only contraceptive (norethindrone 0.35 mg) in healthy premenopausal women. Methods: These phase I studies used a two-period, sequential design, where period 1 included treatment with oral contraceptives, followed by period 2 with contraceptives coadministered with elagolix 150 mg once daily. Results: In study 1, pharmacokinetic exposures for EE in period 2 increased by 30% and the norgestimate metabolites decreased by approximately 15% when coadministered with elagolix. Mean hormone exposure appeared lower for follicle-stimulating hormone (FSH; 31%), luteinizing hormone (LH; 38%), and estradiol (E2; 16%). The percentage of women with consecutive progesterone (P) concentrations above 5 nmol/L was similar in both periods. Norethindrone pharmacokinetic exposures were comparable in both periods. The hormone exposure for LH and FSH was similar, and mean E2 exposure was 32% lower in period 2. The percentage of subjects with consecutive ovulatory P concentrations was also similar in both periods (study 2). Safety and tolerability profiles were unremarkable in both studies. Conclusions: Coadministration of elagolix 150 mg once daily with oral contraceptives containing EE and norgestimate, or norethindrone, resulted in small pharmacokinetic changes in the oral contraceptive components. Similar or lower FSH, LH, and E2 exposures were observed during coadministration, with ovulatory P concentrations also comparable in both periods. The pharmacodynamic profiles of the oral contraceptives were maintained when coadministered with elagolix