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

Abstract

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 original per os formulation.Methods: In vitro disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption. In vivo analysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternatively per os FCT 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 and P = 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 and P < 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC60 min vs. 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.

The first‐generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue

“…Pharmacokinetic profile of three sildenafil formulations according to De Toni et al . (). Serum concentrations are shown for 20 ED patients after taking sildenafil ODF ( IBSA , green line), sildenafil ODT (Pfizer, red line), and sildenafil film‐coated tablets (Pfizer, light blue line).…”

“…Presently, the reason why the different ODT, granule, and ODF formulations have different T max and T onset is unknown. We researched the excipients present in the ODF formulation, the ODT formulation, and the film‐coated tablet formulation (Table ) that are the three formulations studied by De Toni et al ., (). As film‐coated tablets are not done to be crushed in the mouth, the excipients are different from those of ODT and ODF formulations, as shown in Table .…”

“…Another ODF formulation of sildenafil, developed by IBSA (Switzerland) and marketed in Italy by Sofar and IBSA, is described in three recent studies. De Toni et al ., () compared the pharmacokinetics of ODF with ODT (Pfizer) and film‐coated tablets (Pfizer) through a crossover, single‐dose study on 20 Italian males with psychogenic ED (mean age of 31 years). Clinicians asked patients to maintain ODT or ODF under the tongue for 15 min to promote the sublingual route.…”

“…The same study evaluated the adverse effects of the three formulations (De Toni et al ., ), which were headache (14 patients), flushing (18 patients), and nasal congestion (19 patients). The incidence of the latter was similar for all three formulations (8, 5, and 6 with film‐coated tablets, ODT, and ODF, respectively).…”

“…The results revealed differences in mean IIEF scores for erectile function, orgasmic function, sexual desire, and intercourse satisfaction that were significantly in favor of sildenafil film‐coated tablets (100 mg), whereas the mean score for overall satisfaction was in favor of sildenafil ODF (75 mg). In our opinion, no conclusion can be drawn from the above study because it has two crucial flaws: (i) In light of pharmacokinetics data supporting a similar AUC value for sildenafil film‐coated tablet and ODF formulations (De Toni et al ., ), comparison of the two formulations at different dosage does not provide useful information, and (ii) when administering a new drug or a new drug formulation, placebo effects can play a relevant role, especially when a reference drug is already used by patients. Therefore, in the above study, the comparison between the formulations should have been carried out using a masked approach (i.e., by administering film‐coated tablets containing placebo plus ODF sildenafil to one group, and film‐coated tablets containing sildenafil plus ODF placebo to the other group).…”