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Author: Admin | 2025-04-28
Information on paediatric use. 5.2 Pharmacokinetic properties Absorption Sildenafil is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. The mean absolute oral bioavailability is 41% (range 25–63%). After oral dosing of sildenafil AUC and Cmax increase in proportion with dose over the recommended dose range (25–100 mg). When sildenafil is taken with food, the rate of absorption is reduced with a mean delay in tmax of 60 minutes and a mean reduction in Cmax of 29%. Distribution The mean steady state volume of distribution (Vd) for sildenafil is 105 l, indicating distribution into the tissues. After a single oral dose of 100 mg, the mean maximum total plasma concentration of sildenafil is approximately 440 ng/ml (CV 40%). Since sildenafil (and its major circulating N-desmethyl metabolite) is 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for sildenafil of 18 ng/ml (38 nM). Protein binding is independent of total drug concentrations. In healthy volunteers receiving sildenafil (100 mg single dose), less than 0.0002% (average 188 ng) of the administered dose was present in ejaculate 90 minutes after dosing. Biotransformation Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-demethylation of sildenafil. This metabolite has a phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% that of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil. The N-desmethyl metabolite is further metabolised, with a terminal half-life of approximately 4 h. Elimination The total body clearance of sildenafil is 41 l/h with a resultant terminal phase half-life of 3–5 h. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the faeces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose). Linearity/non-linearity After oral dosing of sildenafil AUC and Cmax increase in proportion with dose over the recommended dose range (25–100 mg). Pharmacokinetics in special patient groups Elderly: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 90% higher plasma concentrations of sildenafil and the active N-desmethyl metabolite compared to those seen in healthy younger volunteers (18–45 years). Due to age-differences in plasma protein binding, the corresponding increase in free sildenafil plasma concentration was approximately 40%. Renal insufficiency: In volunteers with mild to moderate renal impairment (creatinine clearance = 3080 ml/min), the pharmacokinetics of sildenafil were not altered after receiving a 50 mg single oral dose. The mean AUC and Cmax of the N-desmethyl metabolite increased
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