title: Safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod in healthy Japanese volunteers.
abstract: This phase 1 study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of losmapimod and its metabolite GSK198602 following single and repeat doses of oral losmapimod in healthy Japanese volunteers. Subjects (n = 41) received single oral doses of losmapimod (2.5, 7.5, 20 mg) or matching placebo on 3 separate days (n = 20) or losmapimod 7.5 mg or matching placebo twice daily for 14 days (n = 21). Assessments included maximum observed plasma concentration (Cmax ), time to Cmax (Tmax ), apparent terminal-phase half-life (t1/ )2 , area under the curve (AUC), and change in C-reactive protein and phosphorylated heat shock protein 27 levels. No serious adverse events occurred during the study, and there were no safety concerns regarding clinical laboratory parameters, 12-lead electrocardiogram, or vital signs. The losmapimod Tmax was 3-4 hours, and the mean t1/2 was approximately 7.9-9.0 hours, with no appreciable difference in Tmax and apparent clearance following oral dosing between dosing regimens. Single and repeat oral doses of losmapimod were well tolerated in healthy Japanese volunteers. The Tmax of GSK198602 was similar to and t1/2 was slightly longer than those of losmapimod. Approximate dose-proportional increases in exposure to losmapimod and GSK198602 were observed in AUC with single-dose administration. Repeat-dose trough concentrations reached steady state within 2 days, with an observed accumulation ratio of 1.56 and 1.91 for losmapimod and GSK198602, respectively.
authors.affiliation: Medicines Development (Clinical Pharmacology), Japan Development & Medical Affairs Division, GlaxoSmithKline K.K., Tokyo, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ino
authors.affiliation: Medicines Development (Clinical Pharmacology), Japan Development & Medical Affairs Division, GlaxoSmithKline K.K., Tokyo, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Biomedical Data Sciences Department, Japan Development & Medical Affairs Division, GlaxoSmithKline K.K., Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Terao
authors.affiliation: Medicines Development (Clinical Pharmacology), Japan Development & Medical Affairs Division, GlaxoSmithKline K.K., Tokyo, Japan.
authors.forename: Harue
authors.initials: H
authors.lastname: Igarashi
authors.affiliation: Medicines Development (Metabolic Pathways and Cardiovascular), Japan Development & Medical Affairs Division, GlaxoSmithKline K.K., Tokyo, Japan.
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Sarai
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D001711:Biotransformation; D003521:Cyclopropanes / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D007564:Japan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009517:New South Wales; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases
keywords: C-reactive protein; Japanese; acute coronary syndrome; heat shock protein 27; losmapimod; p38 mitogen-activated kinase (p38 MAPK)