title: Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel pSYK Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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%).
  
  
  CONCLUSIONS
  The overall safety, pharmacokinetics, and pharmacodynamics profiles of entospletinib support further clinical evaluation.
authors: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors: Srini
authors: S
authors: Ramanathan
authors: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors: Julie A
authors: JA
authors: Di Paolo
authors: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors: Feng
authors: F
authors: Jin
authors: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors: Lixin
authors: L
authors: Shao
authors: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. shringi.sharma@gilead.com.
authors: Shringi
authors: http://orcid.org/0000-0002-8162-5672
authors: S
authors: Sharma
authors: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors: Michelle
authors: M
authors: Robeson
authors: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA.
authors: Brian P
authors: BP
authors: Kearney
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000187:drug effects; D001491:Basophils / Q000187:drug effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D000072377:Syk Kinase / Q000037:antagonists & inhibitors*; D060149:Tetraspanin 30 / Q000096:biosynthesis / Q000187:drug effects; D014638:Vanadates / Q000494:pharmacology; D055815:Young Adult
chemical_list: D060149:Tetraspanin 30; C076715:pervanadate; D014638:Vanadates; D000072377:Syk Kinase