Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel pSYK Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers.

Entospletinib is a selective, reversible, adenosine triphosphate-competitive small-molecule spleen tyrosine kinase (SYK) inhibitor that blocks B cell receptor-mediated signaling and proliferation in B lymphocytes. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of entospletinib in a double-blind, single/multiple ascending dose study in healthy volunteers.,In sequential cohorts, 120 subjects received entospletinib (25-1200 mg; fasted) as single or twice-daily oral doses for 7 days. Along with pharmacokinetics, the study assessed functional inhibition of ex vivo anti-immunoglobulin E-stimulated CD63 expression on basophils and pervanadate-evoked phosphorylated SYK (pSYK) Y525. Safety and tolerability were assessed throughout the study.,Entospletinib was generally well-tolerated over a 48-fold dose range. Adverse events (AEs) were generally mild to moderate, with no AE-driven study drug discontinuations noted. Entospletinib displayed a median plasma half-life of 9-15 h; entospletinib exposures reached a plateau at ≥600 mg twice daily (likely due to solubility-limited absorption) and provided >90% CD63 inhibition at peak concentrations and >60% inhibition at trough concentrations (corresponding pSYK inhibition of >70 and >50%).,The overall safety, pharmacokinetics, and pharmacodynamics profiles of entospletinib support further clinical evaluation.