Bioequivalence of Elagolix/Estradiol/Norethindrone Acetate Fixed‐Dose Combination Product: Phase 1 Results in Healthy Pre‐ and Postmenopausal Women

Abstract

AbstractFixed‐dose combination (FDC) therapies can enhance patient convenience and adherence to prescribed treatment regimens. Elagolix is a novel oral gonadotropin‐releasing hormone receptor antagonist approved for management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Hormonal add‐back therapy can attenuate the reversible hypoestrogenic effects of elagolix. An FDC formulation containing elagolix/estradiol (E2)/norethindrone acetate (NETA) 300/1/0.5 mg as the morning dose and an elagolix 300 mg capsule as the evening dose, were evaluated in 2 bioequivalence studies including the effects of food. Study 1 in premenopausal women assessed the bioavailability of the elagolix 300‐mg capsule relative to the commercially available elagolix 300‐mg tablet. Study 2 in postmenopausal women, elagolix/E2/NETA (300 mg/1 mg/0.5 mg) FDC capsule was assessed relative to the elagolix 300‐mg tablet coadministered with E2/NETA 1‐mg/0.5‐mg tablet, the regimen that was studied in Phase 3 uterine fibroid studies. Under fasting conditions, the test elagolix 300‐mg capsule was bioequivalent to the reference elagolix 300‐mg tablet. Under fasting conditions, the elagolix/E2/NETA FDC capsule was bioequivalent to the coadministered elagolix 300‐mg tablet and E2/NETA 1/0.5‐mg tablet. Following administration of elagolix/E2/NETA FDC capsule after a high‐fat breakfast, elagolix mean maximum concentration (Cmax) and area under the plasma concentration‐time curve (AUC) were 38% and 28% lower, relative to fasting conditions. NETA mean Cmax was 51% lower and AUC from time 0 to infinity was 20% higher, while baseline‐adjusted total estrone mean Cmax and AUC were 46% and 14% lower, respectively. No safety concerns were identified. These results enabled bridging the elagolix/E2/NETA FDC capsule.