Source: Health Products Regulatory Authority (ZA) Revision Year: 2024 Publisher: Macleods Pharmaceuticals SA (Pty) Ltd, Office Block 1, Bassonia Estate Office Park (East), 1 Cussonia Drive, Bassonia Rock, Ext. 12, Alberton, South Africa
Category and Class: A 7.1.5 Vasodilators – peripheral
Pharmacotherapeutic group: Urologicals, Drugs used in erectile dysfunction
ATC code: G04BE03
Sildenafil is an oral therapy for pulmonary arterial hypertension.
Sildenafil is a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) in the smooth muscle of the pulmonary vasculature, where PDE5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation. In patients with pulmonary arterial hypertension this can lead to selective vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation.
Studies in vitro have shown that sildenafil is selective for PDE5. There is a 10-fold selectivity in isoenzyme affinity for PDE5 over PDE6 which is involved in the photo transduction pathway in the retina. There is an 80-fold selectivity over PDE1, and over 700-fold over PDE 2, 3, 4, 7, 8, 9, 10 and 11. In particular, sildenafil has greater than 4 000-fold selectivity for PDE5 over PDE3, the cAMP-specific phosphodiesterase iso form involved in the control of cardiac contractility.
Sildenafil causes mild and transient decreases in systemic blood pressure which, in the majority of cases, do not translate into clinical effects. The mean maximum decrease in supine systolic blood pressure following 100 mg oral dosing of sildenafil was 8,3 mmHg. The corresponding change in supine diastolic blood pressure was 5,3 mmHg. After chronic dosing of 80 mg three times a day to healthy male volunteers, the largest average change from baseline of supine systolic blood pressure was a decrease of 9,0 mmHg. The corresponding change in supine diastolic blood pressure was a decrease of 8,4 mmHg.
After chronic dosing of 80 mg three times a day to patients with systemic hypertension the mean change from baseline in systolic and diastolic blood pressure was a decrease of 9,4 mmHg and 9,1 mm Hg respectively. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension lesser effects in blood pressure reduction were observed (a reduction in both systolic and diastolic pressure of 2 mmHg). This may be due to improvements in cardiac output secondary to the beneficial effects of sildenafil on pulmonary vascular resistance.
Single oral doses of sildenafil up to 100 mg in healthy volunteers produced no clinically relevant effects on ECG. After chronic dosing of 80 mg three times a day to patients with pulmonary arterial hypertension no clinically relevant effects on the ECG were reported.
In a study of the haemodynamic effects of a single oral 100 mg dose of sildenafil in 14 patients with severe coronary artery disease (CAD) (>70% stenosis of at least one coronary artery), the mean resting systolic and diastolic blood pressures decreased by 7% and 6% respectively compared to baseline. Mean pulmonary systolic blood pressure decreased by 9%. Sildenafil showed no effect on cardiac output and did not impair blood flow through the stenosed coronary arteries.
Mild and transient differences in colour discrimination (blue/green) were detected in some subjects following a 100 mg dose, with no effects evident after 2 hours post-dose. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6, which is involved in the photo transduction cascade of the retina. Sildenafil has no significant effect on visual acuity or contrast sensitivity. In a small size placebo- controlled study of patients with documented early age-related macular degeneration (n=9), sildenafil (single dose, 100 mg) demonstrated no significant changes in visual tests conducted (visual acuity, Amsler grid, colour discrimination simulated traffic light, Humphrey perimeter and photo stress).
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 approximately 40% (range 25–63%). After oral three times a day dosing of sildenafil, AUC and Cmax increase in proportion with dose over the dose range of 20–40 mg. After oral doses of 80 mg three times a day slightly more than dose proportional increase in sildenafil plasma levels has been observed.
When sildenafil is taken with a high fat meal, the rate of absorption is reduced with a mean delay in Tmax of 60 minutes and a mean reduction in Cmax of 29%.
The mean steady state volume of distribution (Vss) 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. Since sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins, this results in the mean maximum free plasma concentration for sildenafil of 4,52 ng/ml (9,5 nM). Protein binding is independent of total drug concentrations.
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 PDE 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 hours. In patients with pulmonary arterial hypertension, however, the ratio of UK-103,320 to sildenafil is higher. Plasma concentrations of UK-103,320 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.
The total body clearance of sildenafil is 41 L/h with a resultant terminal phase half-life of 3–5 hours. 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).
Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, with free plasma concentrations approximately 40% greater than those seen in healthy younger volunteers (18–45 years).
In volunteers with mild (CLcr (creatinine clearance) = 50–80 ml/min) and ml/min) renal impairment, the pharmacokinetics of a single oral dose of sildenafil (50 mg) were not altered. In volunteers with severe (CLcr ≤30 ml/min) renal impairment, sildenafil clearance was reduced, resulting in increases in AUC (100%) and Cmax (88%) compared to age-matched volunteers with no renal impairment.
In volunteers with hepatic cirrhosis (Child-Pugh A and B) sildenafil clearance was reduced, resulting in increases in AUC (84%) and Cmax (47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function have not been studied.
Age, gender, race, renal and hepatic function were included as factors in the population pharmacokinetic model to evaluate sildenafil pharmacokinetics in pulmonary arterial hypertension patients. The data set available for the population pharmacokinetic evaluation contained a wide range of demographic data and laboratory parameters associated to hepatic and renal function. None of the factors related to demographics, hepatic or renal function had a statistically significant impact on sildenafil pharmacokinetics in patients with pulmonary arterial hypertension. However, CYP3A4 substrates alone reduced the apparent clearance of sildenafil by 22,3% and in combination with beta-blockers by 37,4%. No other factors had a statistically significant influence on sildenafil 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 Cmin 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.
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