The Effect of Food on the Pharmacokinetics of Sildenafil after Single Administration of a Sublingual Testosterone and Oral Sildenafil Combination Tablet in Healthy Female Subjects

Introduction: Female sexual interest/arousal disorder (FSIAD) affects many women worldwide, but pharmacological treatment options are scarce. A new medicine being developed for FSIAD is an on-demand, dual-route, dual-release drug combination product containing 0.5 mg testosterone (T) and 50 mg sildenafil (S), referred to here as TthornS. Aim: The aim of this study was to compare the effect of a fed and a fasted state on the pharmacokinetics of sildenafil following administration of TthornS. Methods: Eighteen healthy women were administered TthornS under fed and fasted conditions during 2 separate overnight visits in this randomized, open-label, balanced, 2-period, 2-treatment, 2-sequence crossover study. Main Outcome Measures: The pharmacokinetics of sildenafil and its active metabolite N-desmethyl sildenafil were determined over a 24-hour period. Total testosterone was assessed only at a limited number of time points for quality purposes, as sublingual uptake is not expected to be affected by food intake. Results: The observed geometric mean ratios (GMRs) and 90% confidence intervals of sildenafil were not all contained within the prespecified bounds (0.80, 1.25). The GMR (90% CI) for plasma AUC(0-last) was 1.2753 (0.9706-1.6755); for AUC(0-14h), it was 1.7521 (1.0819-2.8374); and for C-max, it was 1.5591 (0.8634-2.8153). Only lower limits of the CIs fell within the bounds. For N-desmethyl sildenafil, the GMR (90% CI) for AUC(0-last) was 0.8437 (0.6738-1.0564); for AUC(0-10h), it was 1.0847 (0.7648-1.5383); and for C-max, it was 1.0083 (0.6638-1.5318). Only the GMRs were contained within bounds. No differences were observed between plasma testosterone C-max and T-max under fed and fasted conditions, which is in line with expectations for a sublingual administration. Clinical Implications: The TthornS combination tablet ruptures too late when taken in a fasted state and should therefore not be taken on an empty stomach. Strengths & Limitations: This is a well-controlled study that provides important insights into the performance characteristics of the delayed-release coating of the combination tablet. The higher variability of the pharmacokinetic parameters in the fasted state was caused by severely delayed rupture in one-third of the women. A reason for this is proposed but the present data do not explain this phenomenon. Conclusion: The pharmacokinetics of sildenafil from this modified-release tablet are more robust under fed conditions as compared to the artificial fasted condition where no food is consumed 10 hours prior to and 4 hours after dosing. The dosing situation under the tested fasting condition does not represent the expected common use of this product. Patients should, however, be instructed not to take the tablet on an empty stomach. Copyright (C) 2019, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.