Sublingual Administration of Sildenafil Oro-dispersible Film: New Profiles of Drug Tolerability and Pharmacokinetics for PDE5 Inhibitors

Objective: Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as originalper osformulation.Methods:In vitrodisaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption.In vivoanalysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternativelyper osFCT or sublingual ODT or ODF, at an equal dosage (50 mg). Pharmacokinetic parameters of Sild and adverse drug reactions experienced after the dosing of each formulation were compared.Results:In vitro, ODF showed the highest time to disaggregation and an increased rate of permeation compared to both ODT and FCT (P= 0.017 andP= 0.008, respectively).In vivo, compared to both FCT and ODT, ODF showed a faster increase of serum Sild levels (serum levels at 15 min from dosing, respectively: 2.24 ± 1.4 ng/ml FCT, 0.5 ± 0.3 ng/ml ODT, and 13.5 ± 9.1 ng/ml ODF;P< 0.01 andP< 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC60minvs. FCT, respectively: 100.0 ± 44.9% FCT, 183.8 ± 75.4% ODT, and 304.2 ± 156.0% ODF). A trend toward lower peak serum levels was observed for ODF. Finally, ODF showed a lower prevalence of headache compared to FCT (1 vs. 35%;P< 0.05) and improved pattern of flushing and nasal congestion.Conclusion:Sublingual Sild ODF improves the drug tolerability through a likely modified pharmacokinetic, suggesting a possible implication also in the clinical efficacy profile. Sublingual administration of oro-dispersible formulations may represent a strategy to ameliorate the adherence to therapy with PDE5i, particularly in patients discouraged by side effects.

Frontiers in pharmacology. 2018 Feb 06*** epublish ***

Luca De Toni, Maurizio De Rocco Ponce, Erica Franceschinis, Stefano Dall'Acqua, Roberto Padrini, Nicola Realdon, Andrea Garolla, Carlo Foresta

Department of Medicine, Unit of Andrology and Reproductive Medicine, University of Padova, Padova, Italy., PharmaTeG - Pharmaceutical Technology Group, Department of Pharmaceutical and Pharmacological Sciences, School of Medicine, University of Padova, Padova, Italy., Department of Pharmaceutical and Pharmacological Sciences, School of Medicine, University of Padova, Padova, Italy., Clinical Pharmacology Unit, Department of Medicine, School of Medicine, University of Padova, Padova, Italy.