Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Antithrombotic Agents; Platelet aggregation inhibitors excl. heparin, ATC code: B01AC09

Mechanism of action
Epoprostenol Sodium, the monosodium salt of epoprostenol, a naturally occurring prostaglandin produced by the intima of blood vessels. Epoprostenol is the most potent inhibitor of platelet aggregation known. It is also a potent vasodilator.

Many of the actions of epoprostenol are exerted via the stimulation of adenylate cyclase, which leads to increased intracellular levels of cyclic adenosine 3’5’ monophosphate (cAMP). A sequential stimulation of adenylate cyclase, followed by activation of phosphodiesterase, has been described in human platelets.
Elevated cAMP levels regulate intracellular calcium concentrations by stimulating calcium removal, and thus platelet aggregation is ultimately inhibited by the reduction of cytoplasmic calcium, upon which platelet shape change, aggregation and the release reaction depends.

Pharmacodynamic effects
An infusion of 4 nanograms/kg/min for 30 minutes has been shown to have no significant effect on heart rate or blood pressure, although facial flushing may occur at these levels.

Intravenous epoprostenol infusions of up to 15 minutes have been found to produce dose-related increases in cardiac index (CI) and stroke volume (SV), and dose-related decreases in pulmonary vascular resistance (PVR), total pulmonary resistance (TPR) and mean systemic arterial pressure (SAPm). The effects of epoprostenol on mean pulmonary artery pressure (PAPm) in patients with PPH were variable and minor.

Clinical efficacy and safety

Chronic continuous infusions of epoprostenol in patients with idiopathic or heritable PAH were studied in 2 prospective, open, randomised trials of 8 and 12 weeks’ duration (N=25 and N=81, respectively) comparing epoprostenol plus conventional therapy to conventional therapy alone. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients; oral vasodilators, diuretics, and digoxin in one half to two thirds of patients; and supplemental oxygen in about half the patients. Except for 2 New York Heart Association (NYHA) functional Class II patients, all patients were either functional Class III or Class IV. As results were similar in the 2 studies, the pooled results are described. The combined baseline 6-minute walk test median values for the conventional therapy group and epoprostenol plus conventional therapy group was 266 meters and 301 meters, respectively.

Improvements from baseline in cardiac index (0.33 vs. -0.12 L/min/m2), stroke volume (6.01 vs. -1.32 mL/beat), arterial oxygen saturation (1.62 vs. -0.85%), mean pulmonary artery pressure (-5.39 vs. 1.45 mm Hg), mean right atrial pressure (-2.26 vs. 0.59 mm Hg), total pulmonary resistance (-4.52 vs. 1.41 Wood U), pulmonary vascular resistance (-3.60 vs. 1.27 Wood U), and systemic vascular resistance (-4.31 vs. 0.18 Wood U) were statistically different between patients who received epoprostenol chronically and those who did not. Mean systemic arterial pressure was not significantly different between the two groups (-4.33 vs. - 3.05 mm Hg). These haemodynamic improvements appeared to persist when epoprostenol was administered for at least 36 months in an open, nonrandomized study.

Statistically significant improvement was observed in exercise capacity (p=0.001), as measured by the 6MWT in patients receiving continuous intravenous epoprostenol plus conventional therapy (N=52) for 8 or 12 weeks compared to those receiving conventional therapy alone (N=54) (combined week 8 and 12 change from baseline – median: 49 vs. -4 meters; mean: 55 vs. -4 meters). Improvements were apparent as early as the first week of therapy. At the end of the treatment period in the 12 weeks study, survival was improved in NYHA functional Class III and Class IV patients. Eight of 40 (20%) patients receiving conventional therapy alone died, whereas none of the 41 patients receiving epoprostenol died (p=0.003).

Chronic continuous infusions of epoprostenol in patients with PAH/SSD were studied in a prospective, open, randomised trial of 12 weeks’ duration comparing epoprostenol plus conventional therapy (N = 56) to conventional therapy alone (N = 55). Except for 5 NYHA functional Class II patients, all patients were either functional Class III or Class IV. Conventional therapy varied among patients and included some or all of the following: anticoagulants in essentially all patients, supplemental oxygen and diuretics in two thirds of the patients, oral vasodilators in 40% of the patients, and digoxin in a third of the patients. The primary efficacy endpoint for the study was improvement in the 6MWT. The median baseline value for the conventional therapy group and epoprostenol plus conventional therapy group was 240 meters and 270 meters, respectively. A statistically significant increase in CI, and statistically significant decreases in PAPm, RAPm, PVR, and SAPm after 12 weeks of treatment were observed in patients who received epoprostenol chronically compared to those who did not.

Over 12 weeks, a statistical difference (p<0.001) in the change from baseline for the 6MWT was observed in the group receiving epoprostenol and conventional therapy as compared to the group receiving conventional therapy alone (median: 63.5 vs. -36.0 meters; mean: 42.9 vs. -40.7 meters).
Improvements were apparent in some patients at the end of the first week of therapy. Increases in exercise capacity were accompanied by statistically significant improvements in dyspnoea, as measured by the Borg Dyspnea Index. At week 12, NYHA functional class improved in 21 of 51 (41%) patients treated with epoprostenol compared to none of the 48 patients treated with conventional therapy alone. However, more patients in both treatment groups (28/51 [55%] with epoprostenol and 35/48 [73%] with conventional therapy alone) showed no change in functional class, and 2/51 (4%) with epoprostenol and 13/48 (27%) with conventional therapy alone worsened.

No statistical difference in survival over 12 weeks was observed in PAH/SSD patients treated with epoprostenol as compared to those receiving conventional therapy alone. At the end of the treatment period, 4 of 56 (7%) patients receiving epoprostenol died, whereas 5 of 55 (9%) patients receiving conventional therapy alone died.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Due to the chemical instability, high potency and short half-life of epoprostenol, no precise and accurate assay has been identified as appropriate for quantifying epoprostenol in biological fluids.

Intravenously administered epoprostenol is rapidly distributed from blood to tissue.
At normal physiological pH and temperature, epoprostenol breaks down spontaneously to 6-oxo-prostaglandin F1 alpha, although there is some enzymatic degradation to other products.

Following the administration of radiolabelled epoprostenol to humans, at least 16 metabolites were found, 10 of which were structurally identified.

Unlike many other prostaglandins, epoprostenol is not metabolised during passage through the pulmonary circulation.

The half-life for the spontaneous breakdown to 6-oxo-prostaglandin F1 alpha in man is expected to be no more than 6 minutes, and may be as short as 2 to 3 minutes, as estimated from in vitro rates of degradation of epoprostenol in human whole blood.

Following the administration of radiolabelled epoprostenol to humans, the urinary and faecal recoveries of radioactivity were 82% and 4%, respectively.