Pharmacokinetics of an oral versus intranasal delivered formulation of the phosphodiesterase type 5 inhibitor vardenafil in healthy men – A Phase 1, Randomized, Open-label, Single-dose, Two-period, Two-treatment, Cross-over Study

Oral therapy with the PDE5 inhibitor vardenafil is an effective, but imperfect treatment for erectile dysfunction (ED). We compared the pharmacokinetics of a new intranasal formulation of vardenafil with an oral tablet equivalent in healthy men. In this Phase 1, single-dose, randomized, open-label, 2-treatment, 2-period crossover study, 19 healthy men (mean age 30.2±5.7 years) were randomized to receive SDS-089 nasal spray or an oral tablet of vardenafil (delivering 5mg and 10mg respectively). After 3-days washout, treatment was reversed. The primary outcome was the bioavailability of vardenafil. Standard pharmacokinetic parameters were computed from the individual plasma concentrations of 18 study participants (one withdrawal). Bioequivalence was accepted if the 90% CI for pharmacokinetic parameters were contained completely within the 80 to 125% range. Following administration, Tmax vardenafil reached peak levels between 0.150 h and 0.250 h post-dose for SDS-089 Nasal Spray and between 0.500 h and 2.500 h post-dose for Vardenafil Tablet. Exposure and maximum plasma concentration of vardenafil were higher for the oral (mean AUC0-t 42.17±25.79 h*ng/mL, mean Cmax 16.74±14.50 ng/mL) versus intranasal formulation (mean AUC0-t 23.10±14.88 h*ng/mL, mean Cmax 12.89±9.07 ng/mL). Mean dose normalized values for AUC0-t were 4.62±2.98 versus 4.22±2.58 h*ng/mL/mg and mean dose normalized values for Cmax 2.58± 1.81 versus 1.67±1.45 ng/mL/mg for the nasal versus oral formulations, respectively. Tmax was shorter (0.17 h, range 0.15-0.25 h) for the nasal versus oral (0.75 h, range 0.50-2.50) formulation. The mean t½ of vardenafil was 4.15±1.67 versus 4.23±1.44 h for the nasal and oral formulations. Parametric analysis of AUC0-t, AUC0-t/D, AUC0-∞, AUC0-∞/D, Cmax, and Cmax/D showed that the investigational drugs did not satisfy the bioequivalence criteria. Overall, adverse events were similar for the two formulations, with more upper-respiratory irritation occurring following intranasal administration. In healthy men, intranasally delivered vardenafil is associated with more rapid Tmax, but similar plasma concentrations without bioequivalence being statistically proven. This differential pharmacokinetic profile has potentially important clinical implications in treating men with ED.