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

ABSTRACT: 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/m2 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.

SUBMITTER: Yang S

PROVIDER: S-EPMC5318329 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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

Yang Shuying S Dumitrescu Teodora Pene TP

Drugs in R&D 20170301 1

<h4>Introduction</h4>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 ...[more]

PMID: 28004376

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Project description:Acute respiratory distress syndrome (ARDS) is common after traumatic brain injury (TBI) and is associated with worse neurologic outcomes and longer hospitalization. However, the incidence and associated causes of ARDS in isolated TBI have not been well studied.We performed a subgroup analysis of 210 consecutive patients with isolated severe TBI enrolled in a prospective observational cohort at a Level 1 trauma center between 2005 and 2014. Subjects required endotracheal intubation and had isolated severe TBI defined by a head Abbreviated Injury Scale (AIS) score of 3 or greater and AIS score lower than 3 in all other categories. ARDS within the first 8 days of admission was rigorously adjudicated using Berlin criteria. Regression analyses were used to test the association between predictors of interest and ARDS.The incidence of ARDS in the first 8 days after severe isolated TBI was 30%. Patients who developed ARDS were administered more crystalloids (4.3 L vs. 3.5 L, p = 0.005) and blood products in the first 12 hours of admission. Patients with ARDS had significantly worse clinical outcomes measured at 28 days, including longer median intensive care unit and hospital stays (4 days vs. 13 days, p < 0.001, and 7.5 days vs. 14.5 days, p < 0.001, respectively). In unadjusted logistic regression analyses, the odds of developing ARDS were significantly associated with head AIS score (odds ratio [OR], 1.8; p = 0.018), male sex (OR, 2.9; p = 0.012), and early transfusion of platelets (OR, 2.8; p = 0.003). These associations were similar in a multivariate logistic regression model.In the era of balanced hemostatic resuscitation practices, severity of head injury, male sex, early crystalloids, and early transfusion of platelets are associated with a higher risk of ARDS after severe isolated TBI. Early transfusion of platelets after severe TBI may be a modifiable risk factor for ARDS, and these findings invite further investigation into causal mechanisms driving this observed association.Prognostic/epidemiologic study, level III.

Project description:BACKGROUND:Improved understanding of the relationship between patient age and acute respiratory distress syndrome (ARDS) development and mortality following traumatic injury may help facilitate generation of new hypotheses about ARDS pathophysiology and the role of novel treatments to improve outcomes across the age spectrum. METHODS:We conducted a retrospective cohort study of trauma patients included in the National Trauma Data Bank who were admitted to an intensive care unit from 2007 to 2016. We determined ARDS incidence and mortality across eight age groups for the entire 10-year study period and by year. We used generalized linear Poisson regression models adjusted for underlying mortality risk (injury mechanism, Injury Severity Score, admission Glasgow Coma Scale score, admission heart rate, and admission hypotension). RESULTS:Acute respiratory distress syndrome occurred in 3.1% of 1,297,190 trauma encounters. Acute respiratory distress syndrome incidence was lowest among pediatric patients and highest among adults aged 35 to 64 years. Acute respiratory distress syndrome mortality was highest among patients 80 years or older (43.9%), followed by 65 to 79 years (30.6%) and 4 years or younger (25.3%). The relative risk of mortality associated with ARDS was highest among the pediatric age groups, with an adjusted relative risk (aRR) of 2.06 (95% confidence interval [CI], 1.72-2.70) among patients 4 years or younger compared with an aRR of 1.51 (95% CI, 1.42-1.62) for the entire cohort. Acute respiratory distress syndrome mortality increased over the 10-year study period (aRR, 1.03 per year; 95% CI, 1.02-1.05 per year), whereas all-cause mortality decreased (aRR, 0.98 per year; 95% CI, 0.98-0.99 per year). CONCLUSIONS:While ARDS development following traumatic injury was most common in middle-aged adults, patients 4 years or younger and 65 years or older with ARDS experienced the highest burden of mortality. Children 4 years or younger were disproportionately affected by ARDS relative to their low underlying mortality following trauma that was not complicated by ARDS. Acute respiratory distress syndrome-associated mortality following trauma has worsened over the past decade, emphasizing the need for new prevention and treatment strategies. LEVEL OF EVIDENCE:Prognostic/epidemiological study, level III.

Project description:OBJECTIVES:To determine risk factors identifiable at hospital arrival associated with acute respiratory distress syndrome development among critically injured children. DESIGN:Retrospective cohort study. SETTING:Level I or II adult or pediatric trauma centers contributing to the National Trauma Data Bank from 2007 to 2016. PATIENTS:Patients less than 18 years admitted to an ICU with traumatic injury. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We determined associations between patient, injury, and clinical characteristics present at hospital arrival with development of acute respiratory distress syndrome recorded as a hospital complication. Acute respiratory distress syndrome occurred in 1.8% of 146,058 critically injured children (n = 2,590). The only demographic factor associated with higher risk of developing acute respiratory distress syndrome on multivariable analysis was African American race (relative risk, 1.42 vs white; 95% CI, 1.13-1.78). Injury characteristics included firearm injuries (relative risk 1.93; 1.50-2.48) and motor vehicle crashes (relative risk, 1.91; 1.57-2.31) relative to falls; spine (relative risk, 1.39; 1.20-1.60), chest (relative risk, 1.36; 1.22-1.52), or lower extremity injuries (relative risk, 1.26; 1.10-1.44); amputations (relative risk, 2.10; 1.51-2.91); and more severe injury (relative risk, 3.69 for Injury Severity Score 40-75 vs 1-8; 2.50-5.44). Clinical variables included abnormal respiratory status (intubated relative risk, 1.67; 1.23-2.26 and hypopnea relative risk, 1.23; 1.05-1.45 and tachypnea relative risk, 1.26; 1.10-1.44) and lower Glasgow Coma Scale score (relative risk, 5.61 for Glasgow Coma Scale score 3 vs 15; 4.44-7.07). CONCLUSIONS:We provide the first description of the incidence of and risk factors for acute respiratory distress syndrome among pediatric trauma patients. Improved understanding of the risk factors associated with acute respiratory distress syndrome following pediatric trauma may help providers anticipate its development and intervene early to improve outcomes for severely injured children.

Dataset Information

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

Publications

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

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