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

Abstract

IntroductionCligosiban is a selective oxytocin receptor antagonist being developed for the treatment of premature ejaculation (PE). AimThree 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. MethodsStudy 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 MeasuresBlood sampling for cligosiban assay and safety assessments were conducted throughout all studies. Cerebrospinal fluid (CSF) samples for cligosiban assay were collected in study 2. ResultsCligosiban 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 ImplicationsCligosiban 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 & LimitationsThree 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. ConclusionCligosiban 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.