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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 lung injury (ALI) and acute respiratory distress syndrome (ARDS) are known complications of injuries in combat casualties, but there has been no review characterizing them. This scoping review aims to map the combat trauma-related ALI/ARDS literature and characterize these conditions in the military population.Data sourcesPubmed was searched from 1969 to April 2022.Study selectionStudies were included if they examined ALI/ARDS or related entities (blast lung injury [BLI], transfusion-related acute lung injury, and acute respiratory failure) in combat trauma patients in the military (U.S. or allied forces).Data extractionStudy years, design, location, number of patients, target outcomes as related to ALI/ARDS or related entities, and results were collected.Data synthesisThe initial search yielded 442 studies, with 22 ultimately included. Literature on ALI/ARDS comes mostly from retrospective data and case studies, with limited prospective studies. The incidence and prevalence of ALI/ARDS range from 3% to 33%, and mortality 12.8% to 33%. BLI, a known antecedent to ALI/ARDS, has an incidence and mortality ranging from 1.4% to 40% and 11% to 56%, respectively. Risk factors for ALI/ARDS include pulmonary injury, inhalation injury, blunt trauma, pneumonia, higher military injury severity score, higher injury severity score, higher fresh frozen plasma volumes, higher plasma and platelet volumes, the use of warm fresh whole blood, female sex, low blood pressure, and tachycardia. Literature has demonstrated the effectiveness in transportation of these patients and the utility of extracorporeal life support.ConclusionsALI/ARDS incidences and prevalences in modern conflict range from 3% to 33%, with mortality ranging from 12.8% to 33%. ALI/ARDS has been associated with injury severity metrics, injury type, resuscitative fluid amount and type, vital signs, and patient demographics. Studies are limited to mostly retrospective data, and more data are needed to better characterize these conditions.

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.

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

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