The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil

Abstract

Aims To investigate the effects of age and renal and hepatic impairment on the pharmacokinetics, tolerability and safety of sildena®l (single 50-mg oral dose) and its major circulating N-desmethyl metabolite, 320. Methods Three open-label, parallel-group studies were conducted. The ®rst study compared sildena®l 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 (CL cr ). 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 speci®ed intervals up to 48 h postdose for assays of sildena®l and UK-103,320, and measurements of protein binding. Results Signi®cant differences in C max 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 C max values 60±70% higher than those for young men, while t 1/2 values were approximately 1 h longer for sildena®l and 2 h longer for UK-103,320. Due to a signi®cantly 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, signi®cant correlations with CL cr were demonstrated for sildena®l oral clearance (CL/F) and C max and UK-103,320 C max and AUC. Pairwise comparisons between subjects with normal renal function and those with severe renal impairment (CL cr <30 ml min x1 ) supported these ®ndings, showing signi®cant increases in C max and AUC for both the parent drug and the metabolite in the severely impaired subjects. The hepatic impairment study demonstrated that the pharmacokinetics of sildena®l were altered in subjects with chronic stable cirrhosis, as shown by a 46% reduction in CL/F and a 47% increase in C max compared with subjects with normal hepatic function, suggesting a reduction in ®rst-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, sildena®l was well tolerated, most adverse events were mild and no subjects discontinued treatment. Conclusions Sildena®l 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.

The Effect of Age on Sildenafil Biotransformation in Rat and Mouse Liver Microsomes

“…Given the prevalence of ED in the elderly population and the widespread use of SIL for ED treatment, the study of age-related differences in the pharmacokinetics of SIL is critical. Muirhead et al (2002) demonstrated a 60 to 70% increase in maximum SIL concentrations in older male subjects, as well as oral clearance values approximately half those observed in young male subjects. The factors that contribute to these age-related changes in pharmacokinetic parameters are not clearly established.…”

Therapeutic Potential of Phosphodiesterase 5 Inhibition for Cardiovascular Disease

“…Thus, concurrent use of sildenafil and drugs inhibiting this pathway, as well as severe renal impairment or hepatic dysfunction, can lead to higher plasma levels. 64,22 Presumably, some of the described side effects can be attributed to supratherapeutic plasma levels of sildenafil.…”

Elderly and drugs: risks and necessity of rational use

“…This drug is cleared almost exclusively by hepatic metabolism and its primary metabolite is N-desmethyl metabolite -UK 103,320 (Muirhead et al, 2002).…”