Silatio 20 Mechanism of Action

Pharmacology: Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart from the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
Pharmacokinetics: 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 three times a day dosing of Sildenafil, AUC and C_max increase in proportion with dose over the dose range of 20-40 mg. After oral doses of 80 mg three times a day a more than dose proportional increase in Sildenafil plasma levels has been observed. In pulmonary arterial hypertension patients, the oral bioavailability of Sildenafil after 80 mg three times a day was on average 43% (90% CI: 27-60%) higher compared to the lower doses.
When Sildenafil is taken with food, the rate of absorption is reduced with a mean delay in T_max of 60 minutes and a mean reduction in C_max of 29% however, the extent of absorption was not significantly affected (AUC decreased by 11%).
Distribution: The mean steady state volume of distribution (V_SS) for Sildenafil is 105 L, indicating distribution into the tissues. After oral doses of 20 mg three times a day, the mean maximum total plasma concentration of Sildenafil at steady state is approximately 113 ng/mL. Sildenafil and its major circulating N-desmethyl metabolite are approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations.
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. The N-desmethyl metabolite is further metabolized, with a terminal half-life of approximately 4 h. In patients with pulmonary arterial hypertension, plasma concentrations of N-desmethyl metabolite are approximately 72% those of Sildenafil after 20 mg three times a day dosing (translating into a 36% contribution to Sildenafil's pharmacological effects). The subsequent effect on efficacy is unknown.
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 feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of administered oral dose).
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=30-80 mL/min), the pharmacokinetics of Sildenafil were not altered after receiving a 50 mg single oral dose. In volunteers with severe renal impairment (creatinine clearance <30 mL/min), Sildenafil clearance was reduced, resulting in mean increases in AUC and C_max of 100% and 88% respectively compared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and C_max values were significantly increased by 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function.
Hepatic insufficiency: In volunteers with mild to moderate hepatic cirrhosis (Child-Pugh class A and B) Sildenafil clearance was reduced, resulting in increases in AUC (85%) and C_max (47%) compared to age-matched volunteers with no hepatic impairment. In addition, N-desmethyl metabolite AUC and C_max values were significantly increased by 154% and 87%, respectively in cirrhotic subjects compared to subjects with normal hepatic function. The pharmacokinetics of Sildenafil in patients with severely impaired hepatic function have not been studied.
Population pharmacokinetics: In patients with pulmonary arterial hypertension, the average steady state concentrations were 20-50% higher over the investigated dose range of 20-80 mg three times a day compared to healthy volunteers. There was a doubling of the C_min compared to healthy volunteers. Both findings suggest a lower clearance and/or a higher oral bioavailability of Sildenafil in patients with pulmonary arterial hypertension compared to healthy volunteers.
Pediatric population: Pharmacokinetic profile of Sildenafil in the pediatric patients, body weight was shown to be a good predictor of drug exposure in children. Sildenafil plasma concentration half-life values were estimated to range from 4.2 to 4.4 hours for a range of 10 to 70 Kg of body weight and did not show any differences that would appear as clinically relevant. C_max after a single 20 mg Sildenafil dose administered PO was estimated at 49, 104 and 165 ng/mL for 70, 20 and 10 Kg patients, respectively. C_max after a single 10 mg Sildenafil dose administered PO was estimated at 24, 53 and 85 ng/mL for 70, 20 and 10 Kg patients, respectively. T_max was estimated at approximately 1 hour and was almost independent from body weight.