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

Abstract

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, 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.

© 2012 GlaxoSmithKline. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Figures

Figure 1

Mean concentration at each time point with standard error bars. , 15 mg orally (PO); , 3 mg intravenously (IV); and , 1 mg IV

Figure 2

Visual predictive check forphosphorylated heat shock protein 27 (pHSP27) direct inhibitory model with observed data. Mean of observed data at each time point with standard error bars and thick continuous line. The median of simulated data at each time point is shown by the thin continuous line. The 90% prediction interval is indicated by the thin dashed lines. , observed data. Left panel shows data for 3 mg IV and right panel 15 mg PO. The model appears to describe the central tendency and variability of the data well, supporting the suitability of the model

Figure 3

AUC0–24vs. change from baseline high-sensitivity C-reactive protein (hsCRP) with smooth (i.e. a lowess fit curve). No exposure–response relationship was demonstrated. The hsCRP values were below the limit of quantification for one subject following 3 mg IV dosing and two subjects following 15 mg PO dosing