First-in-Human Safety and Pharmacokinetic Evaluation of Seralutinib, an Investigational Inhaled Tyrosine-protein Kinase Inhibitor for Pulmonary Hypertension.

OBJECTIVE

First-in-human studies were conducted to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple doses of inhaled seralutinib in healthy participants.

METHODS

Two phase I, randomized, double-blind, placebo-controlled studies were conducted. In Study 1, participants received single ascending doses of seralutinib (3.75-48 mg) or placebo (Part 1) and multiple ascending doses of seralutinib (18 mg BID, 24 mg TID, and 48 mg TID) or placebo for 7 days (Part 2). In Study 2, participants received a single dose of seralutinib 90 mg or placebo (Part 1) and multiple doses of seralutinib (90 mg BID) or placebo for 7 days (Part 2). Sentinel dosing strategy was utilized for all cohorts. Safety was assessed. Seralutinib PK was characterized.

RESULTS

82 healthy participants completed the studies (20 received placebo; 37, single doses of seralutinib; 25, multiple doses of seralutinib BID or TID for 7 days). No serious adverse events (AEs) or AEs leading to withdrawal were reported. Most AEs were mild in severity. Following single and multiple dose inhalations, seralutinib was quickly absorbed (median tmax 5 minutes) into, and rapidly cleared from the systemic circulation. Mean terminal elimination half-life was 3.08-5.75 hours. Seralutinib exposures increased in an approximately dose-proportional manner. Steady-state plasma levels were reached by Day 3 (multiple doses). Minimal accumulation in plasma was observed after multiple days of BID or TID doses.

CONCLUSION

Consistent with its PK profile, seralutinib administered as single or multiple doses was generally well tolerated, with a favorable safety profile in healthy adults.