An open-label, single-dose, randomized, parallel-group study of the safety and relative bioavailability of topical sildenafil cream vs oral sildenafil in healthy male adults

Introduction Oral phosphodiesterase-5 (PDE5) inhibitors are commonly prescribed for erectile dysfunction (ED), but have limiting side effects, particularly for men with serious cardiovascular disease. Topical sildenafil cream was developed based on the hypothesis that local genital application would result in less systemic exposure and fewer side effects compared to oral sildenafil citrate. The objective of this study was to describe the systemic pharmacokinetics (PK) and safety of topical sildenafil cream 3.6% in healthy men, applied to the penis with and without male condom use, compared to oral sildenafil. Methods Phase 1, open-label, single-dose, randomized, parallel-group design. Participants were randomized 1:1:1:1:1 to 36 mg of sildenafil in 1 g of cream or 71 mg of sildenafil in 2 g of cream self-applied to the penile skin with or without male condom use vs a 50 mg oral dose of sildenafil. Blood and orthostatic vital signs were taken prior to dosing and up to 32 hours post dosing. Safety was assessed by treatment emergent adverse events (TEAEs) and physical exam. Single dose PK parameters for plasma sildenafil and its active metabolite, N-desmethyl sildenafil were calculated. Results Sixty-two men received study medication. All TEAEs (n = 14) were mild. Half of the TEAEs (7/14, 50%), including headache (n = 4) and flushing (n = 2), resulted from oral dosing. The mean maximum plasma concentration (Cmax) of sildenafil after topical application (all 4 dosing groups) ranged from 969 to 1274 pg/mL, compared to 238 000 pg/mL with oral administration. Dose proportionality assessments using the geometric means of Cmax and systemic exposure (AUClast) and total amount of drug absorbed over the entire elimination period (AUCinf) indicated that the geometric means of all 3 PK parameter estimates were similar with a 2-fold increase in dose, indicating a less than dose-proportional increase. Similar results were observed with or without condom use in the topical application groups. Compared to oral administration, the relative bioavailability of sildenafil after topical application ranged from 2.55% to 3.20%. Similar results were observed for the N-desmethyl sildenafil. Discussion This safety and PK study provides early data on the comparison of Sildenafil cream topical dosing to the oral dosing referent. Topically applied Sildenafil Cream was safe and well tolerated by healthy men. Topical sildenafil cream use was associated with lower systemic exposure compared to oral sildenafil use.