Selexipag

Indications

Selexipag is prescribed for the management of pulmonary arterial hypertension (PAH). Its primary function is to decelerate disease progression and diminish the risk of hospitalization, thereby enhancing the quality of life for affected individuals.

Pharmacodynamics

At the highest recommended dose of 1600 mcg administered twice daily, selexipag has not demonstrated any clinically significant prolongation of the QT interval. Both selexipag and its active metabolite exhibit concentration-dependent inhibition of platelet aggregation in vitro, with IC50 values of 5.5 µM and 0.21 µM, respectively. However, during treatment with selexipag at clinically relevant doses in healthy subjects, platelet aggregation parameters showed no observable changes.

Absorption

Following oral administration, selexipag reaches peak plasma concentrations between 1 and 3 hours, while its active metabolite peaks between 3 and 4 hours. The presence of food has been noted to impair absorption, leading to a delayed time in reaching maximum concentration and causing approximately a 30% reduction in peak plasma levels. Nonetheless, overall exposure to selexipag remains largely unaffected by food intake.

Metabolism

Selexipag is metabolized into its active form through the hydrolysis of acylsulfonamide by hepatic carboxylesterase 1. It also undergoes oxidative metabolism, catalyzed by the enzymes CYP3A4 and CYP2C8, resulting in the formation of hydroxylated and dealkylated products. The glucuronidation of the active metabolite involves UGT1A3 and UGT2B7 enzymes. Other circulating metabolites constitute less than 3% of the total drug-related material, indicating minimal presence aside from the active metabolite.

Mechanism of Action

Selexipag functions as a selective agonist for the prostacyclin (IP) receptor, also known as PGI2. Pulmonary arterial hypertension is characterized by reduced levels of prostacyclin and prostacyclin synthase, the enzyme responsible for prostacyclin production within the lungs. Prostacyclin itself is renowned for its powerful vasodilatory properties, along with significant anti-proliferative, anti-inflammatory, and anti-thrombotic effects. Consequently, IP receptor agonists are strongly justified as a therapeutic approach. Unlike PGI2 or its analogues, selexipag is structurally unique, demonstrating high specificity for the IP receptor. Upon administration, selexipag is metabolized by the enzyme carboxylesterase 1, resulting in the formation of an active metabolite, ACT-333679, which exhibits approximately 37 times the potency of selexipag. Both selexipag and its active metabolite maintain selectivity for the IP receptor, distinguishing them from other prostanoid receptors.