Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate‐release oral formulation in healthy volunteers

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single‐center, randomized, double‐blind, placebo‐controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate‐release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty‐two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post‐dose and mean terminal elimination half‐life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady‐state plasma exposure measures were observed where evaluable, with mean steady‐state peak‐to‐trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half‐life values ranged from 17.5–18.4 h, reflecting ∼1.7‐fold (QD dosing) and ∼2.6‐fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate‐release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady‐state peak‐to‐trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended‐release formulation to facilitate QD dosing.