Interaction of sildenafil and indinavir when co-administered to HIV-positive patients

Objectives: The prevalence of erectile dysfunction in HIV-infected men is e stimated to be 33%. Sildenafil citrate (Viagra; Pfizer Ltd, Sandwich, Kent, UK) is the first oral drug for this condition. Since sildenafil and the pr otease inhibitors are both metabolized by, and act as inhibitors of cytochr ome P450 3A4, we evaluated the pharmacokinetics of the combination sildenaf il plus indinavir in HIV-infected patients. Design and methods: Six patients at steady state in treatment with indinavi r participated in the study. On the first day blood samples for indinavir a ssay were drawn at times 0, 1, 2, 3, 4, 6 and 8 h after dosing. On the seco nd study day patients received a single dose of 25 mg of sildenafil in addi tion to their routine morning medication. Blood samples were taken as descr ibed. Separated plasma was stored at -80 degrees C until analysis by high p erformance liquid chromatography. In a parallel study, the effect of indina vir, ritonavir, saquinavir and nelfinavir on the in vitro hepatic metabolis m of sildenafil was assessed. Results: The geometric mean area under the concentration curve for 0-8 h (A UC(0-8h)) and maximum plasma concentration (C-max) for indinavir were 19.69 mu g/ml h (range, 9.19-31.99 mu g/ml h) and 7.02 mu g/ml (range, 2.33-16.1 7 mu g/ml), respectively, on the first study day. In the presence of silden afil, the mean AUC(0-8h) and C-max of indinavir were 22.37 mu g/ml h [range , 10.08-37.25 mu g/ml h; 95% confidence interval (CI) for difference betwee n means, -15 to 13.25) and 9.11 mu g/ml (range, 3.41-22.78 mu g/ml; 95% CI, -13 to 6.37), respectively. The geometric mean AUC(0-8h) and C-max for sildenafil were 1631 ng/ml h (ra nge, 643-2970 ng/ml h) and 384 ng/ml (range, 209-766 ng/ml) respectively. T he AUC for sildenafil was 4.4 times higher than data from historical contro ls given either 50mg or 100mg of sildenafil and dose normalized to 25 mg. I ndinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro [ concentration producing 50% inhibition of control enzyme activity (IC50) = 0.39 +/- 0.17 mu M, mean +/- SD]. Conclusions: Go-administration of sildenafil 25 mg did not significantly al ter the plasma indinavir revels. However, plasma sildenafil AUC was markedl y increased in the presence of indinavir compared with historical controls. From the in vitro data, the mechanism of increase is indinavir inhibition of the hepatic metabolism of sildenafil. The magnitude of this interaction suggests a lower starting dose of sildenafil may be more appropriate in thi s clinical setting. (C) 1999 Lippincott Williams & Wilkins.