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

Aims  To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil 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 sildenafil (n=12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil 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 sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies.

Results  The calculated absolute oral bioavailability of sildenafil 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 significance. 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 nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient.

Conclusions  Sildenafil 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 significance. Across the dose range of 25–200 mg, systemic exposure increased in a slightly greater than dose‐proportional manner.