Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir

Aims To investigate the effect of the antiretroviral protease inhibitors sa quinavir (soft gelatin capsule) and ritonavir on the pharmacokinetic proper ties and tolerability of sildenafil and to investigate the effect of silden afil on the steady-state pharmacokinetics of saquinavir and ritonavir. Methods Two independent, 8 day, open, randomized, placebo-controlled, paral lel-group studies (containing a double-blind crossover phase) were conducte d at Pfizer Clinical research units (Canterbury, UK. and Brussels, Belgium) . Twenty-eight healthy male volunteers entered each study. In each study, v olunteers were randomized (n = 14 per group) to receive sildenafil on day 1 followed by a 7-day treatment period (days 2-8) with saquinavir or placebo (Study I) or ritonavir or placebo (Study II). Sildenafil or placebo (Study I and Study II) was administered alternately on day 7 or day 8, depending on initial randomization. The effect of saquinavir and ritonavir on the pha rmacokinetics of sildenafil and its primary circulating metabolite (UK-103, 320) and the effect of single-dose sildenafil on the steady-state pharmaco kinetics of saquinavir (1200 mg three times daily) and ritonavir (500 mg tw ice daily) were determined. The safety and tolerability of sildenafil coadm inistered with saquinavir or ritonavir were also assessed. Results Both protease inhibitors significantly increased C-max, AUC, t(max) and t(1/2) values for both sildenafil and UK-103, 320. Ritonavir showed a significantly greater affect than saquinavir with increases in sildenafil A UC and C-max, of 11-fold (95% CI: 9.0, 12.0) and 3.9-fold (95% CI: 3.2, 4.9 ), respectively. This compared with increases of 3.1-fold (95% CI: 2.5, 4.0 ) and 2.4-fold (95% CI: 1.8, 3.3) for coadministration with saquinavir. In contrast, the steady-state pharmacokinetics of saquinavir and ritonavir wer e unaffected by sildenafil. The increases in systemic exposure to sildenafi l and UK-103, 320 were not associated with an increased incidence of advers e events or clinically significant changes in blood pressure, heart rate or ECG parameters. Conclusions These results indicate that both saquinavir and ritonavir modif y the pharmacokinetics of sildenafil presumably through inhibition of CYP3A 4. The more pronounced effect of ritonavir may be attributed to its additio nal potent inhibition of CYP2C9. No change in safety or tolerability was ob served when sildenafil was coadministered with either protease inhibitor. H owever, given the extent of the interactions, a lower sildenafil starting d ose (25 mg) should be considered for patients receiving saquinavir and it i s recommended not to exceed a maximum single dose of 25 mg in a 48 h period for patients receiving ritonavir.