title: Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers.
abstract: OBJECTIVE
  The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 mitogen-activated protein kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome indication. Pharmacokinetics (PK) following IV dosing were characterized, and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and phosphorylated heat shock protein 27 (pHSP27) and high-sensitivity C-reactive protein were explored.
  
  
  METHODS
  Healthy volunteers received 1 mg losmapimod IV over 15 min (n = 4) or 3 mg IV over 15 min followed by a washout period and then 15 mg orally (PO; n = 12). Pharmacokinetic parameters were calculated by noncompartmental methods. The PK/PD relationships were explored using modelling and simulation.
  
  
  RESULTS
  There were no deaths, nonfatal serious adverse events or adverse events leading to withdrawal. Headache was the only adverse event reported more than once (n = 3 following oral dosing). Following 3 mg IV and 15 mg PO, Cmax was 59.4 and 45.9 μg l(-1) and AUC0-∞ was 171.1 and 528.0 μg h l(-1) , respectively. Absolute oral bioavailability was 0.62 [90% confidence interval (CI) 0.56, 0.68]. Following 3 mg IV and 15 mg PO, maximal reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30 min and 4 h, respectively. There was a 17% decrease (95% CI 9%, 24%) in high-sensitivity C-reactive protein 24 h following oral dosing. A direct-link maximal inhibitory effect model related plasma concentrations to pHSP27 concentrations.
  
  
  CONCLUSIONS
  A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in acute coronary syndrome as rapid exposure is achieved.
authors.affiliation: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA 19406, USA. april.m.barbour@gsk.com
authors.forename: April M
authors.initials: AM
authors.lastname: Barbour
authors.forename: Lea
authors.initials: L
authors.lastname: Sarov-Blat
authors.forename: Gengqian
authors.initials: G
authors.lastname: Cai
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Fossler
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Sprecher
authors.forename: Johann
authors.initials: J
authors.lastname: Graggaber
authors.forename: Adam T
authors.initials: AT
authors.lastname: McGeoch
authors.forename: Jo
authors.initials: J
authors.lastname: Maison
authors.forename: Joseph
authors.initials: J
authors.lastname: Cheriyan
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D002097:C-Reactive Protein / Q000378:metabolism; D015331:Cohort Studies; D003521:Cyclopropanes / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000097:blood; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D055551:HSP27 Heat-Shock Proteins; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases