Introduction
Palopag Tablet 200 mg used for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce risk of hospitalization. PAH is a relatively rare disease with usually a poor prognosis requiring more treatment options to prolong long-term outcomes. Its active metabolite, ACT-333679 (MRE-269), act as agonists of the prostacyclin receptor to increase vasodilation in the pulmonary circulation and decrease elevated pressure in the blood vessels supplying blood to the lungs.
Uses
Palopag Tablet 200 mg is a non prostanoid IP prostacyclin receptor agonist used to treat pulmonary arterial hypertension.
Palopag Tablet 200 mg is indicated for the treatment of pulmonary arterial hypertension (PAH) to delay disease progression and reduce risk of hospitalization.
Associated Conditions
Pharmacodynamics
At the maximum tolerated dose of 1600 mcg twice per day, selexipag was not found to prolong the QT interval to a clinically relevant extent. Both selexipag and its metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with IC50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters following multiple dose administration of selexipag in healthy patients.
Mechanism of Action
Palopag Tablet 200 mg is a selective prostacyclin (IP, also called PGI2) receptor agonist. The key features of pulmonary arterial hypertension include a decrease in prostacyclin and prostacyclin synthase (enzyme that helps produce prostacyclin) in the lung. Prostacyclin is a potent vasodilator with anti-proliferative, anti-inflammatory, and anti-thrombotic effects; therefore, there is strong rationale for treatment with IP receptor agonists. Palopag Tablet 200 mg is chemically distinct as it is not PGI2 or a PGI2 analogue and has high selectivity for the IP receptor. It is metabolized by carboxylesterase 1 to yield an active metabolite (ACT-333679) that is approximately 37 times more potent than selexipag. Both selexipag and its metabolite are selective for the IP receptor over other prostanoid receptors.
Absorption
After oral administration, maximum concentrations of selexipag and its metabolite were observed to be reached at 1-3 and 3-4 hours, respectively. Absorption was impaired in the presence of food, resulting in delayed time to maximum concentration as well as ~30% lower peak plasma concentration. However, exposure was not found to be significantly affected by food.
Protein Binding
Both selexipag and its active metabolite are highly protein bound, approximately 99%.
Route of Elimination
93% in feces, 12% in urine.
Half Life
Palopag Tablet 200 mg's terminal half life is 0.8-2.5 hours. The active metabolite's terminal half life is 6.2-13.5 hours.
Clearance
On average, 35 L/hour.
Toxicity
A 40-70% increase in exposure was observed in subjects with severe renal impairment.
Food Interactions
No interactions found.
Dosage
Pediatric use: Safety and effectiveness in pediatric patients have not been established.
Geriatric use: No overall differences have been observed.
Hepatic impairment: For Moderate hepatic impairment patients starting dose is 200 mcg once daily, increase the dose by 200 mcg once daily at weekly intervals to the highest tolerated dose up to 1600 mcg. Avoid use of Palopag Tablet 200 mg in patients with severe hepatic impairment (Child-Pugh class C).
