Mechanism of Action
Sildenafil is an 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 hypertension, this
can lead to 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. Its effect
is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6,
>80-fold for PDE1, >700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10,
and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important
because PDE3 is involved in control of cardiac contractility. Sildenafil is only
about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina
and involved in the phototransduction pathway of the retina. This lower selectivity
is thought to be the basis for abnormalities related to color vision observed with
higher doses or plasma levels (see Pharmacodynamics).
In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE5
is also found in other tissues including vascular and visceral smooth muscle and
in platelets. The inhibition of PDE5 in these tissues by sildenafil may be the basis
for the enhanced platelet anti-aggregatory activity of nitric oxide observed in vitro,
and the mild peripheral arterial-venous dilatation in vivo.
Pharmacokinetics and Metabolism
Absorption and Distribution: REVATIO is rapidly absorbed after oral administration,
with a mean absolute bioavailability of 41% (25-63%). Maximum observed plasma concentrations
are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted
state. When REVATIO 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. Sildenafil
and its major circulating N-desmethyl metabolite are both approximately 96% bound
to plasma proteins. Protein binding is independent of total drug concentrations.
Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4
(major route) and cytochrome P450 2C9 (CYP2C9, minor route) hepatic microsomal isoenzymes.
The major circulating metabolite results from N-desmethylation of sildenafil, and
is, itself, further metabolized. This metabolite has a phosphodiesterase selectivity
profile similar to sildenafil and an in vitro potency for PDE5 approximately
50% of the parent drug. In healthy volunteers, plasma concentrations of this metabolite
are approximately 40% of those seen for sildenafil, so that the metabolite accounts
for about 20% of sildenafil's pharmacologic effects. In patients with pulmonary
arterial hypertension, however, the ratio of the metabolite to sildenafil is higher.
Both sildenafil and the active metabolite have terminal half-lives of about 4 hours.
The concomitant use of potent cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir
ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine,
is associated with increased plasma levels of sildenafil (see DOSAGE AND ADMINISTRATION
and PRECAUTIONS/Drug Interactions).
After either oral or intravenous administration, sildenafil is excreted as metabolites
predominantly in the feces (approximately 80% of the administered oral dose) and
to a lesser extent in the urine (approximately 13% of the administered oral dose).
Pharmacokinetics in Special Populations
Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil,
resulting in approximately 84 and 107% higher plasma concentrations of
sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in
healthy younger volunteers (18-45 years). Due to age-differences in plasma protein binding,
the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl
metabolite were 45% and 57%, respectively.
Renal Insufficiency: In volunteers with mild (CLcr =50-80 mL/min) and moderate
(CLcr =30-49 mL/min) renal impairment, the pharmacokinetics of a single oral dose
of sildenafil (50 mg) was not altered. In volunteers with severe (CLcr <30 mL/min)
renal impairment, sildenafil clearance was reduced, resulting in approximately doubling
of AUC and Cmax compared to age-matched volunteers with
no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values were
significantly increased 200 % and 79 %, respectively, in subjects with severe renal
impairment compared to subjects with normal renal function.
Hepatic Insufficiency: In volunteers with hepatic cirrhosis (Child-Pugh class
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. Patients with severe hepatic impairment (Child-Pugh class
C) have not been studied.
Population pharmacokinetics
Age, gender, race, and renal and hepatic function were included as factors assessed
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 with hepatic and renal function. None of these factors had
a statistically significant impact on sildenafil pharmacokinetics in patients with
pulmonary hypertension.
In patients with pulmonary hypertension, the average steady-state concentrations
were 20-50% higher when compared to those of healthy volunteers. There was also
a doubling of Cmin levels compared to healthy volunteers.
Both findings suggest a lower clearance and/or a higher oral bioavailability of
sildenafil in patients with pulmonary hypertension compared to healthy volunteers.
Pharmacodynamics
Effects of REVATIO on Blood Pressure: Single oral doses of sildenafil (100
mg) administered to healthy volunteers produced decreases in supine blood pressure
(mean maximum decrease in systolic/diastolic blood pressure of 8/5 mmHg). The
decrease in blood pressure was most notable approximately 1-2 hours after dosing,
and was not different from placebo at 8 hours. Similar effects on blood pressure
were noted with 25 mg, 50 mg and 100 mg doses of sildenafil, therefore the effects
are not related to dose or plasma levels within this dosage range. Larger effects
were recorded among patients receiving concomitant nitrates (see CONTRAINDICATIONS).
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 t.i.d. to patients with pulmonary
arterial hypertension, no clinically relevant effects on ECG were reported.
After chronic dosing of 80 mg t.i.d. sildenafil to healthy volunteers, the largest
mean change from baseline in supine systolic and supine diastolic blood pressures
was a decrease of 9.0 mmHg and 8.4 mmHg, respectively.
After chronic dosing of 80 mg t.i.d. sildenafil to patients with systemic hypertension,
the mean change from baseline in systolic and diastolic blood pressures was a decrease
of 9.4 mmHg and 9.1 mmHg, respectively.
After chronic dosing of 80 mg t.i.d. sildenafil to patients with pulmonary arterial
hypertension, lesser reductions than above in systolic and diastolic blood pressures
were observed (a decrease in both of 2 mmHg).
Effects of REVATIO on Vision: At single oral doses of 100 mg and 200 mg,
transient dose-related impairment of color discrimination (blue/green) was detected
using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak
plasma levels. This finding is consistent with the inhibition of PDE6, which is
involved in phototransduction in the retina. An evaluation of visual function at
doses up to 200 mg revealed no effects of REVATIO on visual acuity, intraocular
pressure, or pupillometry.