Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality

Abstract

Aims To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildena®l citrate. Methods Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildena®l (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildena®l and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n=34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildena®l (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildena®l were also assessed in all of these studies. Results The calculated absolute oral bioavailability of sildena®l was 41% (90% CI: 36 ±47). Food slowed the rate of absorption, delaying mean t max by approximately 1 h and reducing C max by 29% (90% CI: 19±38). Systemic exposure, as assessed by the mean area under the plasma concentration±time curve (AUC), was reduced by 11% (90% CI: 6±16). These food effects were not considered to be of clinical signi®cance. There was statistical evidence of nonproportionality in C max and AUC over the dose range 25±200 mg. However the degree of nonproportionality was small, with predicted increases in C max and AUC of 2.2-and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsigni®cant. Sildena®l was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions Sildena®l had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical signi®cance. Across the dose range of 25±200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.

Early sildenafil dose optimization and personalized instruction improves the frequency, flexibility, and success of sexual intercourse in men with erectile dysfunction

“…23,24 However, recent empirical studies, in which objective and subjective measures of erection hardness and duration of erections were used, revealed a much longer amount of time that men with ED can achieve and maintain an erection of sufficient hardness for having successful sexual intercourse: up to 12 h after a dose of sildenafil. 25,26 We show that the effects of sildenafil can last up to 24 h, much longer than the traditionally recommended 4 h. Although only 18% of men had successful second sexual intercourse at the end of phase 2, a relatively high proportion (440%) of these men had successful second sexual intercourse attempts more than 4 h after their first sexual intercourse attempt.…”

Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease

“…The oral bioavailability of sildenafil amounts to 41% 63 because of a hepatic first-pass effect. It is metabolized by the cytochrome P450 3A4 pathway, which is known to be inhibited by a number of (in part commonly prescribed) drugs (for a list, see ref 22) and also by certain dietary components.…”

Evaluation of Pharmacokinetic and Pharmacodynamic Drug–Drug Interaction of Sacubitril/Valsartan (LCZ696) and Sildenafil in Patients With Mild‐to‐Moderate Hypertension

“…N‐desmethyl‐sildenafil is a pharmacologically active metabolite of sildenafil with similar terminal half‐life, has ∼50% potency and ∼40% plasma concentration of its parent compound, and accounts for 20% of its pharmacological effects. Given the high degree of observed variability (46%), the marginal decrease in C max of N‐desmethyl‐sildenafil is not considered clinically relevant 16, 17…”

“…A validated liquid chromatography, tandem mass spectroscopy (LC‐MS/MS) method was used for quantification of sildenafil, N‐desmethyl‐sildenafil, and sacubitril/valsartan analytes in plasma 1, 36. The lower limit of quantification values were 1.00 ng/mL for sildenafil, N‐desmethyl‐sildenafil, and sacubitril; 20.0 ng/mL for sacubitrilat; and 10.0 ng/mL for valsartan 2, 16…”