A phase 1, open-label, within-participant dose-escalation study to evaluate the safety and pharmacokinetics of topical sildenafil cream in healthy postmenopausal women

OBJECTIVES: To describe the systemic and local genital safety and pharmacokinetics (PK) of topical sildenafil cream, 3.6% (sildenafil cream) among healthy postmenopausal women. METHODS: This was a phase 1, open-label, within-participant, dose-escalation study. Participants (N=21) were exposed to a single dose of placebo cream and three doses of sildenafil cream containing 50, 100, and 200 mg of sildenafil citrate. There was a 14-16-day washout period between each dose. Blood was obtained for analysis of sildenafil and its active metabolite, N-desmethyl sildenafil, plasma levels, before dosing and for up to 32 hours after each dose. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs), vulvar-vaginal irritation scores, electrocardiograms, laboratory testing and orthostatic vital signs. RESULTS: Twenty-one Hispanic women (mean age: 57 y) were enrolled and 19 completed all 4 treatment arms. All doses of sildenafil cream were well tolerated. All TEAEs were mild. There were no cardiac TEAEs or episodes of symptomatic orthostatic hypotension. At the maximum 200 mg dose, the geometric mean (coefficient of variation % [CV%]) maximum plasma concentration (Cmax) of sildenafil was 5,262 (42) pg/mL occurring at 2 hours post-dosing. The Cmax after the 100 mg dose, the dose used in a subsequent phase 2b study in premenopausal women, was 3,810 (41) pg/mL. Both concentrations are ∼2 orders of magnitude lower than those seen in men after a single 100 mg oral dose (450,000 pg/mL). CONCLUSIONS: These data support further clinical development of topical sildenafil cream for the treatment of female sexual arousal disorder in postmenopausal women and are consistent with phase 2b data among premenopausal women and their male sexual partners.