A population pharmacokinetic analysis of sildenafil citrate in patients with erectile dysfunction.

Aims: To analyse the pharmacokinetics of sildenafil citrate in patients with erectile dysfunction in order to characterize covariate relationships and assist in the development of rational dosage strategies.

Methods: A population pharmacokinetic sampling strategy was incorporated into five phase III clinical study protocols. Overall, 2077 patients, 1335 of whom received sildenafil, were asked to take an additional dose of study drug before their scheduled clinic visits on four or five occasions throughout the study duration. A single plasma sample was obtained at random times postdose (range 1--7 h), and a total of 4582 samples were assayed (average 3.4 samples per individual).

Results: For the population average patient (age 58 years; aspartate transaminase [AST], 24 IU l(-1); weight, 87 kg; not receiving CYP3A4 potential inhibitors), typical values for sildenafil (mean +/- SE) were 58.5 +/- 1.4 l h(-1) for apparent clearance (CL/F), 310 +/- 6.92 l for volume of distribution (V/F), and 2.6 +/- 0.176 h(-1) for first-order absorption constant (ka). The value for ka is associated with meal consumption within 2 h predose, at all other times ka was equivalent to an instantaneous bolus administration. The interindividual variabilities were 29% for CL/F, 20% for V/F, and 210% for ka. Over a dose range of 25--100 mg sildenafil, the pharmacokinetics exhibited dose proportionality. There was evidence of nonproportionality (40% increase on average) in relative bioavailability with respect to the 200-mg dose (P<0.001) relative to the other doses. Age, AST concentration, and co-administration with CYP3A4 potential inhibitors significantly influenced CL/F of sildenafil (P<0.001, for each relationship). For age and AST, the extent of the linear relationships (extrapolated from population average values) included a 4% decrease in CL/F for every decade increase and a 6% decrease in CL/F for every 10-unit increase, respectively. Following co-administration of CYP3A4 potential inhibitors, a 14% decrease in CL/F was estimated. Only body weight was found to significantly (P<0.001) influence V/F (a 6% increase in V/F for every 10-kg increase).

Conclusions: The pharmacokinetics of, and covariate influences on, sildenafil in patients with erectile dysfunction were shown to be consistent with those demonstrated in phase I volunteer studies.