Single‐ and Multiple‐Day Dosing Studies to Investigate High‐Dose Pharmacokinetics of Epelsiban and Its Metabolite, GSK2395448, in Healthy Female Volunteers

Abstract

Open-label single-and double-blind repeat-dose studies in healthy female volunteers were conducted to investigate the pharmacokinetics (PK) and safety/tolerability of epelsiban total daily doses ranging from 600 to 900 mg. In 1 study (n = 12), epelsiban was dosed at 300 or 450 mg twice daily (every 12 hours) for a single day. In the repeat-dose doubleblind study, epelsiban and placebo were administered to 31 subjects as 200 mg 3 times daily, 300 mg 3 times daily (TID), or 450 mg twice daily (BID) for 14 days. After both single and 14 daily repeat doses, the PK profiles for epelsiban and its metabolite, GSK2395448, remained linear at all administered doses. The exposures at a given total daily dose were also similar between BID and TID dosing regimens. Exposure (AUC 0-τ ), based on dosing intervals, for both epelsiban and GSK2395448 was similar. However, compared with morning dosing, C max was lower after evening dosing, possibly because of a food effect. The highest accumulation of epelsiban and GSK2395448 exposures (AUC 0-τ ) was approximately 34% for each after repeat dosing, consistent with the short half-life. At total daily doses of 600 and 900 mg, epelsiban was generally well tolerated, and there were no significant safety concerns identified.

Exploring the Endocrine Mechanisms in Adenomyosis: From Pathogenesis to Therapies

“…Several compounds were developed such as Barusiban, Nolasiban, Retosiban, and Epelsiban. A phase I trial on Epelsiban, initially tested for embryo transfer, proved it to be well tolerated and with no significant safety concerns [165]. Its efficacy was investigated in phase II (NCT02794467), but results were inconclusive as the trial was halted by the sponsor for priority reasons, rather than safety concerns or regulatory interactions [166].…”

The Present and the Future of Medical Therapies for Adenomyosis: A Narrative Review

“…Treatment with Linzagolix reduced adenomyotic lesion size and dysmenorrhea burden, ultimately leading to improved quality of life [59]. Another GnRH antagonist, Elagolix, is currently being developed for the long-term treatment of endometriosis and uterine leiomyomas [55,[60][61][62]. Elagolix has been shown to regress the size of fundal adenomyoma, with an improvement in clinical symptoms and the resolution of pelvic pain [63].…”

Current and Prospective Treatment of Adenomyosis

“…Oxytocin antagonists are being investigated for the use in adenomyosis treatment because overexpression of oxytocin receptor has been demonstrated in uteri with adenomyosis [ 50 ]. In a phase I trial, Epelsiban, a selective oxytocin receptor antagonist, was tested on a population of healthy women and was found to be well tolerated with no significant safety concerns [ 51 ]. Further trials on patients with adenomyosis are needed to evaluate the efficacy.…”