Safety, tolerability, pharmacokinetics, and pharmacodynamics of Losmapimod following a single intravenous or oral dose in healthy volunteers.

Barbour AM, Sarov-Blat L, Cai G, Fossler MJ, Sprecher DL, Graggaber J, McGeoch AT, Maison J, Cheriyan J.
Journal   Br J Clin Pharmacol.
Species  
Analytes Measured   HSP27
Matrix Tested   Stimulated whole blood
Year   2012
Volume  
Page Numbers  
Application   Phosphoproteins
Abstract
AIM: The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 MAP-kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome (ACS) indication. Pharmacokinetics (PK) following IV dosing were characterized and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and pHSP27 and hsCRP were explored.

METHODS: Healthy volunteers received 1mg losmapimod IV over 15 minutes (n=4) or 3mg IV over 15 minutes followed by a washout period and then 15mg orally (PO) (n=12). PK parameters were calculated by non-compartmental methods. PK/PD relationships were explored using modelling and simulation.

RESULTS: There were no deaths, non-fatal SAEs, or AEs leading to withdrawal. Headache was the only AE reported more than once, n=3 following oral dosing. Following 3mg IV and 15 mg PO, Cmax was 59.4 μg/L and 45.9 μg/L and AUC(0-inf) was 171.1 μg·hr/L and 528.0 μg·hr/L, respectively. Absolute oral bioavailability was 0.62 (90% CI 0.56, 0.68). Following 3mg IV and 15mg PO, maximum reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30 minutes and 4 hours, respectively. There was a 17% decrease (95% CI 9%, 24%) in hsCRP 24 hours following oral dosing. A direct link maximum-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 ACS as rapid exposure is achieved.

View Publications

Related Products

R-PLEX Human HSP27/HspB1 Antibody Set
HSP27/HspB1 | Human
R-PLEX Human HSP27/HspB1 Assay
HSP27/HspB1 | Human
Singleplex
Browse Our Products

By Analytes
By Applications
Search
Customer Service/Orders


Scientific/Technical Support


Instrument Support


Company Headquarters