Population Pharmacokinetics and Pharmacodynamics Modelling of Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome

INTRODUCTION: Dilmapimod is a potent p38 mitogen-activated protein kinase (MAPK) inhibitor and was investigated in a study (NCT00996840) for its anti-inflammatory effect in non-head injury trauma patients at risk for developing acute respiratory distress syndrome (ARDS). The purpose of this paper is to present the details of the development of a population pharmacokinetic (PK) model, an empirical population placebo response model, and the exploration of a PK/pharmacodynamic (PD) model of dilmapimod. METHODS: A population PK model was developed to characterise the PK profile of dilmapimod in this patient population; the potential effect of available covariates on the PK of dilmapimod was evaluated. An empirical population placebo response model was conducted, and a population PK/PD model was explored to evaluate the relationship between dilmapimod concentration and C-reactive protein (CRP) (a systemic biomarker of p38 inhibition). All analyses were performed using NONMEM software. RESULTS: Following intravenous dosing, dilmapimod was quickly distributed to peripheral compartments and then slowly eliminated. The plasma concentration of dilmapimod was adequately described by a three-compartment model. It increased approximately proportionally to the increase in dose. The population clearance (CL) parameter value was 35.87 L/h, and the steady-state volume of distribution (Vss) [sum of the volume of distribution of the central compartment (Vc) and of the peripheral compartments V2 and V3] was 160 L. The effect of body mass index (BMI) on CL and inter-compartment clearance (Q2) was found statistically significant, with an increase in BMI of 1 kg/m(2) resulting in a 1.79 L/h and 0.52 L/h increase in CL and Q2, respectively. The CRP profile post injury was adequately described by an indirect response model, with a sharp increase in the CRP levels following injury, followed by them slowly diminishing. Data exploration indicated potential drug effects of dilmapimod on inhibiting the production of CRP levels; however, the current small dataset did not show a statistically significant improvement in the PK/PD modelling. CONCLUSION: The population PK modelling adequately evaluated the dilmapimod plasma concentration–time profiles in severe trauma subjects at risk for ARDS, and BMI was found to be a significant covariate in the PK model. An indirect response model was adequate to describe the production and degradation of CRP levels in these subjects.