The first-generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue

Abstract

Background: Erectile dysfunction (ED) is a relatively frequent disease that negatively impacts the overall quality of life, well-being, and relationships. Although the use of phosphodiesterase 5 inhibitors (PDE5is) has revolutionized the treatment of ED, a high percentage of ED patients discontinue PDE5i treatment.

Objectives: (i) To analyze the reasons for patient dissatisfaction leading to PDE5i discontinuation; (ii) analyze the pharmacokinetics of new formulations focusing on the time needed to reach an effective plasma concentration of PDE5is (T_onset ) following drug intake; and (iii) summarize the physicochemical properties of sildenafil to understand which excipients may increase the absorption rate.

Material and methods: An online PubMed literature search was conducted to identify English language publications from inception to January 2019.

Results: The main reasons for patient dissatisfaction when using PDE5is on demand are the relatively long T_onset after taking vardenafil and sildenafil, including formulations such as film-coated tablets, fine granules, orally disintegrating tablets (ODTs), and oral thin films (ODFs). The relatively long T_onset , further worsened when accompanied by eating, highlights the following: (i) the need for planning intercourse, determining partner-related issues; (ii) issues when having sex before the maximum effect of the drug; and (iii) lower drug-related placebo effects. Some data suggest that sildenafil is a 'difficult' molecule, but T_onset can be improved following absorption by buccal mucosa using appropriate excipients.

Conclusions: We conclude that several ODT and ODF formulations can improve the 'discretion' issue because they are taken without water, but they have similar pharmacokinetics to corresponding film-coated tablet formulations. One ODF formulation of sildenafil was characterized by a shorter T_onset and could potentially increase patient satisfaction following treatment. However, more clinical studies are needed to confirm the findings. Surfactants and ascorbic acid appear to be crucial excipients for achieving a high absorption rate, but more studies are needed.

Keywords: ODF formulation; OTF formulation; PDE5 inhibitors; erectile dysfunction; excipients; pharmacokinetic.

Figure 1

Advantages and disadvantages of plasma concentration curves of PDE5is taken on demand. (A) Schematic diagram of examples of plasma concentration curves that might be obtained with different formulations (A, A1, B, C, and D curves of PDE5is). (B) Magnification of the curves depicted in A during the first hour. The time needed to reach the minimum effective concentration is T_onset, the maximum drug plasma concentration is C_max, and the time at which C_max is reached is T_max (indicated only for the specified formulations). Desired and unwanted effects of PDE5is are depicted. Within the therapeutic windows, lower and higher PDE5i concentrations were considered to give an EHGS grade 3 erection and grade 4 erection (fully rigid erection), respectively. Figure shows the clinical effects of a PDE5i depend on dose, half‐life, and formulation of a drug, determining different plasma concentration curves. Both A and A1 reach a plasma concentration sufficiently high to give a fully rigid erection (EHGS grade 4) after 5–10 min (despite the different T_max), and their concentrations are sufficiently high for long enough to allow satisfactory sexual activity. The plasma concentrations of B and C, derived from different doses of the same drug formulations, are both suboptimal for adverse effects or efficacy, respectively. The plasma concentration of formulation D is suboptimal for duration of the wanted effect.

Figure 2

Reasons for the discontinuation of PDE5is according to Corona et al. (2016b).

Figure 3

Pharmacokinetic profile of three sildenafil formulations according to De Toni et al. (2018). 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). Modified from Fig. 3 of De Toni et al. (2018). ^a p < 0.01 vs. film‐coated tablets; ^b p < 0.05 vs. ODT.