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Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers
Author(s) -
Barbour April M.,
SarovBlat Lea,
Cai Gengqian,
Fossler Michael J.,
Sprecher Dennis L.,
Graggaber Johann,
McGeoch Adam T.,
Maison Jo,
Cheriyan Joseph
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12063
Subject(s) - tolerability , pharmacokinetics , medicine , dosing , pharmacodynamics , pharmacology , adverse effect , cmax , bioavailability , oral administration
Aims 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 , C max was 59.4 and 45.9 μg l −1 and AUC 0–∞ 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.