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.

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