RESUMO
Elagolix is an oral gonadotropin-releasing hormone receptor antagonist indicated for the management of endometriosis-associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late-stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug-drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter-mediated DDIs, elagolix area under the curve (AUC) increased by â¼2-fold following coadministration with ketoconazole and by â¼5- and â¼2-fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%-59%) and increased digoxin AUC by 32% (23%-41%). Elagolix decreased rosuvastatin AUC by 40% (29%-50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150-mg once-daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200-mg twice-daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P-glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.
Assuntos
Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Receptores LHRH/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/agonistas , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Citocromo P-450 CYP2B6/metabolismo , Indutores do Citocromo P-450 CYP2B6/administração & dosagem , Indutores do Citocromo P-450 CYP2B6/farmacocinética , Inibidores do Citocromo P-450 CYP2C9/administração & dosagem , Inibidores do Citocromo P-450 CYP2C9/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Esquema de Medicação , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/farmacologia , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Pré-Menopausa , Pirimidinas/sangue , Pirimidinas/farmacologia , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Adulto JovemRESUMO
The clinical pharmacology of elagolix was extensively evaluated in clinical studies in healthy subjects and in women with endometriosis. Elagolix pharmacokinetics (PK) show significant population variability, however they are minimally affected by patients' baseline characteristics and demographics, except for clinically relevant extrinsic and intrinsic factors such as coadministrated strong organic anion transporting polypeptide (OATP) 1B1 inhibitors and severe hepatic impairment, which are contraindications for the use of elagolix. These studies enabled a comprehensive understanding of elagolix mechanism of action and the downstream pharmacodynamic (PD) effects on gonadotropin and ovarian hormones, as well as full characterization of the PK/PD (PKPD) relationships of elagolix at various dosages, including the approved 150 mg once daily and 200 mg twice daily dosing regimens for the management of moderate to severe pain associated with endometriosis. Several model-based analyses have contributed to understanding of the benefit-risk profile of elagolix in patients with endometriosis, through characterization of the exposure relationship with responder rates, with changes in bone mineral density over time, as well as the interaction with coadministered drugs. Collectively, these studies and analyses served as supportive evidence for the effectiveness of the approved dosages and provided general dosing instructions of the first approved oral gonadotropin-releasing hormone receptor antagonist.
Assuntos
Endometriose/tratamento farmacológico , Antagonistas de Hormônios/farmacocinética , Hidrocarbonetos Fluorados/farmacocinética , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Pirimidinas/farmacocinética , Receptores LHRH/antagonistas & inibidores , Administração Oral , Densidade Óssea/efeitos dos fármacos , Interações Medicamentosas/fisiologia , Endometriose/complicações , Endometriose/metabolismo , Feminino , Hormônio Liberador de Gonadotropina/efeitos dos fármacos , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Humanos , Hidrocarbonetos Fluorados/administração & dosagem , Hidrocarbonetos Fluorados/farmacologia , Hepatopatias/complicações , Transportadores de Ânions Orgânicos/metabolismo , Dor/tratamento farmacológico , Dor/etiologia , Farmacogenética , Farmacologia Clínica , Pirimidinas/administração & dosagem , Pirimidinas/farmacologia , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the safety and efficacy of elagolix vs. placebo and elagolix with low-dose E2/progestogen add-back therapy. DESIGN: Proof-of-concept, dose-ranging, multiple-cohort study. SETTING: Clinics. PATIENT(S): Premenopausal women with fibroids and heavy menstrual bleeding (menstrual blood loss [MBL] >80 mL per cycle). INTERVENTION(S): Three months' treatment with elagolix alone: 100 mg twice daily (BID), 200 mg BID, 300 mg BID, 400 mg once daily (QD), or 600 mg QD (all but the 600 mg QD arm were placebo controlled); or elagolix plus add-back therapy: 200 mg BID plus continuous low-dose E2 0.5 mg/norethindrone acetate 0.1 mg or elagolix 300 mg BID plus E2 1 mg continuously and cyclical P 200 mg. MAIN OUTCOME MEASURE(S): Least-squares mean percentage change in MBL; adverse events (AEs). RESULT(S): Mean age was 41.8 years; 73.8% were black; mean baseline MBL was 267 mL. Of randomized women (elagolix alone, n = 160; placebo, n = 50; elagolix with add-back therapy, n = 61), 228 of 271 completed the 3-month treatment period. The MBL percentage change from baseline to last 28 days was significantly greater with elagolix alone (range, -72% to -98%; dose-dependent reduction was highest with 300 mg BID) vs. placebo (range, -8% to -41%); mean percentage changes with add-back regimens were -80% to -85%. Overall AEs were dose independent (elagolix alone, 70.0%-81.3%) but lower with placebo (56.0%) and add-back regimens (55.6%-70.6%). Hot flush was the most common AE (elagolix alone, 45.5%-62.5%; placebo, 12.0%; add-back regimens, 18.5%-26.5%). CONCLUSION(S): Elagolix significantly reduced heavy menstrual bleeding in women with fibroids. Low-dose add-back regimens substantially reduced flushing. CLINICAL TRIAL REGISTRATION NUMBER: NCT01441635.