A Randomized Open-Label Study of Relugolix Alone or Relugolix Combination Therapy in Premenopausal Women

• Published in: Clinical pharmacokinetics Vol. 62; no. 8; pp. 1169 - 1182
• Main Authors: Lukes, Andrea, Migoya, Elizabeth, Johnson, Brendan, Lee, Tien-Yi, Li, Yulan, Arjona Ferreira, Juan Camilo
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2023; Springer Nature B.V
• Subjects: Bone density; Combination therapy; Drug dosages; Endometriosis; Estradiol - therapeutic use; Estrogens; Female; Fibroids; Humans; Internal Medicine; Medicine; Medicine & Public Health; Menstruation; NCT; NCT04978688; Norethindrone - adverse effects; Norethindrone Acetate; Original; Original Research Article; Osteoporosis; Pharmacodynamics; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Phenylurea Compounds; Womens health
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-023-01269-9

Background and Objective Relugolix is a gonadotropin-releasing hormone receptor antagonist. Relugolix 40-mg monotherapy is associated with vasomotor symptoms and long-term bone mineral density loss due to hypoestrogenism. This study assessed whether the addition of estradiol (E2) 1 mg and norethindrone acetate (NETA) 0.5 mg to relugolix 40 mg (relugolix combination therapy) provides systemic E2 concentrations in the 20–50 pg/mL range to minimize these undesirable effects. Methods This was a randomized, open-label, parallel-group study to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of relugolix 40 mg alone or in combination with E2 1 mg and NETA 0.5 mg in healthy premenopausal women. Eligible women were randomized 1:1 to receive relugolix alone or relugolix plus E2/NETA for 6 weeks. Study assessments included pharmacokinetic parameters of E2, estrone, and relugolix in both treatment groups, and norethindrone in the relugolix plus E2/NETA treatment group at weeks 3 and 6. Results Median E2 24 h average concentrations with the relugolix plus E2/NETA group ( N = 23) were 31.5 pg/mL, 26 pg/mL higher compared with the relugolix-alone group (6.2 pg/mL) ( N = 25). There were 86.4% of participants in the relugolix plus E2/NETA group who had E2 average concentrations exceeding 20 pg/mL, the threshold expected to minimize bone mineral density loss, compared with 21.1% in the relugolix-alone group. Both treatments were generally safe and well tolerated. Conclusions Relugolix 40 mg in combination with E2 1 mg and NETA 0.5 mg provided systemic E2 concentrations within a range expected to minimize the risk of undesirable effects of hypoestrogenism associated with the administration of relugolix alone. Clinical Trial Registration Clinicaltrials.gov identifier no. NCT04978688. Trial registration date: 27 July, 2021; retrospectively registered.