Aims: To investigate the effects of age and renal and hepatic impairment on the pharmacokinetics, tolerability and safety of sildenafil (single 50-mg oral dose) and its major circulating N-desmethyl metabolite, UK-103,320.
Methods: Three open-label, parallel-group studies were conducted. The first study compared sildenafil pharmacokinetics, safety and toleration in 15 healthy young male subjects (mean age 30 years; range 19--45 years) to 15 healthy elderly male subjects (mean age 70 years; range 65--81 years). The second study included eight male volunteers with normal renal function and 16 male volunteers with varying degrees of renal impairment as assessed by measurement of creatinine clearance (CLcr). The third study included 12 male volunteers with normal hepatic function and 12 male volunteers with chronic stable hepatic cirrhosis (Child-Pugh A and B). For all three studies, blood and urine samples were collected predose and at specified intervals up to 48 h postdose for assays of sildenafil and UK-103,320, and measurements of protein binding.
Results: Significant differences in Cmax and AUC were observed between the young and the elderly subjects for both the parent drug and the metabolite. In the elderly, AUC values were approximately twice as high and Cmax values 60--70% higher than those for young men, while t1/2 values were approximately 1 h longer for sildenafil and 2 h longer for UK-103,320. Due to a significantly smaller unbound fraction of drug in the elderly, free drug concentrations were only approximately 40% higher in the elderly group compared to the young group. In the renal impairment study, significant correlations with CLcr were demonstrated for sildenafil oral clearance (CL/F) and Cmax and UK-103,320 Cmax and AUC. Pairwise comparisons between subjects with normal renal function and those with severe renal impairment (CLcr<30 ml min-1) supported these findings, showing significant increases in Cmax and AUC for both the parent drug and the metabolite in the severely impaired subjects. The hepatic impairment study demonstrated that the pharmacokinetics of sildenafil were altered in subjects with chronic stable cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in Cmax compared with subjects with normal hepatic function, suggesting a reduction in first-pass metabolism as well as systemic clearance. The increase in systemic exposure for UK-103,320 was approximately twice that seen for the parent drug. In all three studies, sildenafil was well tolerated, most adverse events were mild and no subjects discontinued treatment.
Conclusions: Sildenafil pharmacokinetics were affected by age and by renal and hepatic impairment, suggesting that a lower starting dose of 25 mg should be considered for patients with severely compromised renal or hepatic function.