Single dose sublingual testosterone and oral sildenafil versus a dual-route/dual-release fixed-dose combination tablet:a pharmacokinetic comparison

AIM: To compare the pharmacokinetic profiles of two formulations of a combination drug product containing 0.5 mg testosterone and 50 mg sildenafil for Female Sexual Interest/Arousal Disorder. The prototype (formulation 1), consists of a testosterone solution for sublingual administration, and a sildenafil tablet that is administered 2.5 hours later. The dual-route/dual-release fixed-dose combination tablet (formulation 2) employs a sublingual and an oral route for systemic uptake. This tablet has an inner-core of sildenafil with a polymeric time-delay coating and an outer polymeric coating containing testosterone. It was designed to increase dosing practicality and decrease potential temporal nonadherence through circumventing the relatively complex temporal dosing scheme.METHODS: 12 healthy premenopausal subjects received both formulations randomly on separate days. Blood was sampled frequently to determine the pharmacokinetics of free testosterone, total testosterone, dihydrotestosterone, sildenafil and N-desmethyl-sildenafil.RESULTS: Formulation 2 had a higher maximum concentration (Cmax ) for testosterone, 8.06 ng/ml (95% confidence interval [CI] 6.84-9.28) and higher area under the plasma concentration-time curve (AUC), 7.69 ng*h/mL (95% CI 6.22-9.16) than formulation 1; 5.66 ng/ml (95% CI 4.63-6.69) and 5.12 ng*h/mL (95% CI 4.51-5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173 ng/ml (95% CI 126-220) and a lower AUC, 476 ng*h/mL (95% CI 401-551) than formulation 1; 268 ng/ml (95% CI 188-348) and 577 ng*h/mL (95% CI 462-692), respectively. Formulation 2 released sildenafil after 2.75 h (95% CI 2.40-3.10).CONCLUSIONS: The dual-route/dual-release fixed-dose combination tablet fulfilled its design-criteria and is considered suitable for further clinical testing.