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

Abstract

Aim: The aim was 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 h 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 non-adherence through circumventing the relatively complex temporal dosing scheme.

Methods: Twelve 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(-1) (95% confidence interval [CI] 6.84, 9.28) and higher area under the plasma concentration-time curve (AUC), 7.69 ng ml(-1) h (95% CI 6.22, 9.16) than formulation 1, 5.66 ng ml(-1) (95% CI 4.63, 6.69) and 5.12 ng ml(-1) h (95% CI 4.51, 5.73), respectively. Formulation 2 had a lower Cmax for sildenafil, 173 ng ml(-1) (95% CI 126, 220) and a lower AUC, 476 ng ml(-1) h (95% CI 401, 551) than formulation 1, 268 ng ml(-1) (95% CI 188, 348) and 577 ng ml(-1) h (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.

What is already known about this subject: Female sexual interest/arousal disorder (FSIAD) is a significant problem impacting psychological well-being, but the pharmacotherapeutic options for this problem are lacking. The combined, on-demand, sublingual administration of low dose sublingual testosterone and oral administration of sildenafil is a novel pharmacotherapeutic option under development for FSIAD. In proof-of-concept trials, these compounds were successfully administered via different dosage forms (sublingual and oral) at different time points (separated by 2.5 h) because of their markedly different pharmacokinetic-pharmacodynamic profiles. For future larger scale studies and the clinical practice, this raises obvious adherence issues.

What this study adds: A newly developed dual route/dual release fixed dose combination tablet containing testosterone and sildenafil mimics the pharmacokinetic profile of these components when they are administered as different dosage forms, 2.5 h apart. This combination tablet is a suitable final pharmaceutical drug product that will be used in future studies.

Keywords: Lybrido; combination-tablet; pharmacokinetics; sildenafil; testosterone.

Figure 1

CONSORT flow diagram

Figure 2

Mean total testosterone plasma concentration–time profiles. Formulation 1: separate dosage forms prototype, Formulation 2: dual‐route/dual‐release fixed‐dose combination tablet

Figure 3

Mean free testosterone plasma concentration–time profiles. Formulation 1: separate dosage forms prototype, Formulation 2: dual‐route/dual‐release fixed‐dose combination tablet

Figure 4

Mean dihydrotestosterone plasma concentration–time profiles. Formulation 1: separate dosage forms prototype, Formulation 2: dual‐route/dual‐release fixed‐dose combination tablet

Figure 5

Mean sildenafil plasma concentration–time profiles. Formulation 1: separate dosage forms prototype, Formulation 2: dual‐route/dua‐release fixed‐dose combination tablet

Figure 6

Mean N‐desmethyl‐sildenafil plasma concentration–time profiles. Formulation 1: separate dosage forms prototype, Formulation 2: dual‐route/dual‐release fixed‐dose combination tablet