Pharmacokinetics, Safety, and Tolerability of Multiple Doses of the Novel Oxytocin Receptor Antagonist Cligosiban in Development for Premature Ejaculation: Two Randomized Clinical Trials in Healthy Subjects

Background: Cligosiban (formerly IX-01) is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). Aim: To investigate the plasma pharmacokinetics, safety, and tolerability of multiple oral doses of cligosiban in healthy male subjects; measure the amount of cligosiban in semen; and evaluate the potential of cligosiban to modulate CYP3A4. Methods: Both studies were double-blind, placebo-controlled, parallel group designs involving sequential cohorts of 12 subjects each. Cligosiban dosage regimens were 100 mg, 400 mg, 800 mg, 1200 mg, 1,600 mg and 2,400 mg once daily for 10 days, administered as an aqueous dispersion. Outcomes: Blood samplings for cligosiban assays and safety assessments were performed throughout both studies. Semen was collected on day 9 at 2-4 hours postdose in study 1 only. Safety assessments included monitoring of adverse events, 12-lead electrocardiography, vital signs, and laboratory safety assessments. Urine samples for assessment of the 6b-hydroxycortisol/cortisol ratio were collected before dosing on days 1 and 10. Results: Cligosiban was rapidly absorbed after both single and multiple dosing, with maximum plasma concentrations typically measured at 1-3 hours postdose. The terminal half-life was approximately 12 hours, and steady state was achieved by day 3. Exposure increased approximately proportionally to dose after single dosing but less than proportionally after multiple dosing. Accumulation ratios were higher at the lower doses compared with higher doses (2.3 at 100 mg vs 1.1 at 2,400 mg). The mean amount of cligosiban in semen ranged from 0.22 to 2.01 mu g over the 100-1,200 mg dose range (<0.0003% of the administered dose). There were no meaningful differences in the urinary 6b-hydroxycortisol/cortisol ratio after multiple dosing with cligosiban. Cligosiban appeared to be well tolerated at all dose levels. Clinical Implications: Cligosiban is well tolerated following once-daily dosing over a wide dose range and does not appear to modulate CYP3A4 activity, suggesting limited potential for perpetrating drug-drug interactions via this mechanism. Strengths & Limitations: The 2 controlled trials show good toleration and pharmacokinetic data, including negligible amounts of cligosiban in semen at doses expected to be therapeutic. Toleration of cligosiban will need to be confirmed in studies in patients with PE. Conclusion: Cligosiban showed a good safety profile at doses predicted to be therapeutic or supratherapeutic along with a pharmacokinetic profile appropriate for as-required or once-daily dosing. There was no evidence that cligosiban inhibited or induced CYP3A4 at doses up to 2,400 mg. Copyright (C) 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.