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 6ß-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 µg over the 100-1,200 mg dose range (<0.0003% of the administered dose). There were no meaningful differences in the urinary 6ß-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. Muirhead GJ, Osterloh IH, Whaley S, et al. 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. J Sex Med 2019;16:213-222.

Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist-Cligosiban-in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects.

INTRODUCTION: Cligosiban is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). AIM: Three clinical studies investigated the pharmacokinetics (including effect of food and formulation), central penetration, safety, and tolerability of single oral doses of cligosiban in healthy subjects. METHODS: Study 1 was a double-blind, randomized, placebo-controlled, crossover design in 3 cohorts of 10 subjects each. Single doses of 0.3-2,400 mg cligosiban were administered as aqueous solutions or dispersions under fasting and fed (800 mg only) conditions. Studies 2 and 3 were open-label, randomized, crossover designs in 12 subjects each. Study 2 investigated 800 mg cligosiban administered as capsules and aqueous dispersion under fasting conditions, and capsules under fed conditions. Study 3 investigated 1,600 mg cligosiban administered as caplets and aqueous dispersion under fasting conditions, and caplets under fed conditions. MAIN OUTCOME MEASURES: Blood sampling for cligosiban assay and safety assessments were conducted throughout all studies. Cerebrospinal fluid (CSF) samples for cligosiban assay were collected in study 2. RESULTS: Cligosiban was rapidly absorbed under fasting conditions with peak concentrations generally occurring within 1-2 hours post-dose regardless of formulation. Maximum observed plasma concentration (Cmax) and area under the concentration time curve extrapolated to infinity (AUC0-∞) increased approximately dose-proportionally from 0.3-10 mg, but sub-proportionally from 30-2,400 mg. Cligosiban exposure was similar when administered as a dispersion or capsule (800 mg) under fasted conditions, but higher (87% increase) when administered as a caplet compared to the dispersion (1,600 mg). Food decreased the rate of absorption for all 3 formulations (median time to Cmax 3-6 hours compared to 1-2 hours fasted) but increased the extent of absorption (Cmax and AUC0-∞ increased by 75-149% and 33-49%, respectively). Cligosiban was detected in CSF at concentrations approximately 40% of unbound plasma concentrations. Cligosiban was well tolerated at all doses. CLINICAL IMPLICATIONS: Cligosiban is well tolerated over a wide dose range, and has the pharmacokinetic properties to be taken as required prior to sexual intercourse in men with PE and to antagonize the oxytocin receptor in the brain and spinal cord. STRENGTHS & LIMITATIONS: Three controlled trials show similar toleration and pharmacokinetic data. Cligosiban in CSF indicates its likely presence in all central nervous system tissue. These data need to be investigated and confirmed in multiple-dose studies prior to investigation in phase-II studies in men with PE. CONCLUSION: Cligosiban had a good safety/tolerability profile at doses predicted to be therapeutic or supra-therapeutic and a pharmacokinetic profile appropriate for "as-needed" dosing for men with PE. Osterloh IH, Muirhead GJ, Sultana S, et al. Pharmacokinetics, Safety, and Tolerability of Single Oral Doses of a Novel Oxytocin Receptor Antagonist-Cligosiban-in Development for Premature Ejaculation: Three Randomized Clinical Trials in Healthy Subjects. J Sex Med 2018;15:1547-1557.