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Pharmacokinetic Evaluation to Optimize Infliximab Monotherapy with Personalized Pharmacodynamic Biomarkers

使用个性化药效生物标志物优化英夫利昔单抗单一疗法的药代动力学评估

基本信息

批准号：
9768437
负责人：
Phillip P Minar
金额：
$ 11.93万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768437
关键词：
Abdominal Pain Abscess Adolescent Adult Affect Aminoglycoside Antibiotics Anti-Tumor Necrosis Factor Therapy Antibodies Antigens Bayesian Modeling Biological Assay Biological Markers Blood Blood Tests Characteristics Child Childhood Chronic Clinical Clinical Decision Support Systems Colitis Complex Computer software Concentration measurement Crohn&apos s disease Custom Data Development Diarrhea Disease Disease remission Dose Down-Regulation Drug Exposure Drug Kinetics Drug Monitoring Epithelial Evaluation Failure Fistula Friends Funding Goals Grant Growth Hypoalbuminemia Individual Inflammation Inflammatory Inflammatory Bowel Diseases Infusion procedures Intestines Intuition Investigation Knowledge Large Intestine Maintenance Malignant Neoplasms Modeling Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Operative Surgical Procedures Patient-Focused Outcomes Patients Pediatric Crohn&apos s disease Pediatrics Pharmaceutical Preparations Pharmacodynamics Phase Phenytoin Plasma Proteins Population Process Proteomics Provider Randomized Controlled Clinical Trials Randomized Controlled Trials Regimen Relapse Reporting Scheme Schools Secondary to Selection for Treatments Serum Albumin Small Intestines Source System TNF gene Testing Therapeutic Time Treatment Efficacy Treatment Failure Ulcerative Colitis United States Weight Work base burden of illness clinical decision support clinical practice clinical remission cohort dashboard dose individualization effective therapy healing immunogenicity improved individual patient infliximab innovation neutrophil novel novel marker pharmacodynamic biomarker pharmacodynamic model pharmacokinetic model prevent primary endpoint receptor response secondary endpoint specific biomarkers trial comparing user-friendly

项目摘要

PROJECT SUMMARY Personalizing medication dose and dosing intervals for the individual patient with inflammatory bowel disease (IBD) would revolutionize treatment. Crohn’s disease is a relapsing and remitting disease of the large and small intestines that results in progressive inflammation and eventual damage to the bowel. Infliximab, and similar medications that target tumor necrosis factor-alpha (TNFα) in Crohn’s disease patients, can reverse epithelial damage, promote bowel healing and prevent unwanted Crohn’s sequela such as fistula or abscess formation. In children and young adolescents with Crohn’s disease, there has been a paradigm shift in anti-TNF use in order to improve rates of sustained remission and reverse growth failure. While therapeutic drug monitoring has improved the overall durability of infliximab, lifetime rates of surgery for intestinal strictures have remained stagnant with conventional, weight-based dosing. More recent pharmacokinetic studies in adults and children with Crohn’s disease have found infliximab clearance is affected by antigen load (inflammatory burden with TNFα), patient weight, serum albumin, fecal loss of drug and immunogenicity (antibodies to drug). With this substantial variability with infliximab clearance, many clinicians utilize dynamic dosing strategies to account for individual pharmacokinetics such as more frequent dosing intervals for hypoalbuminemia or increasing the dose from 5 to 10 mg/kg for severe colitis. We hypothesize that incorporating patient-specific characteristics and novel blood biomarkers as covariates will result in more accurate prediction of infliximab clearance supporting the use of a Bayesian adaptive-dosing approach in clinical practice. To test this hypothesis, we have proposed a pharmacokinetic evaluation of a rigorously monitored pediatric Crohn disease cohort who have provided longitudinal biospecimens during the first year of infliximab therapy. In Aim 1, we will develop a pharmacokinetic model based on significant covariates that influence infliximab clearance during induction. In Aim 2, we will construct a pharmacokinetic model based on significant covariates that influence infliximab clearance during maintenance. In conclusion, there is a critical knowledge gap between the integration of pharmacodynamic biomarkers with infliximab dosing strategies and even greater provider variability between timing of therapeutic drug monitoring and the subsequent dosing decisions. Our overarching goal is to minimize these current gaps with improved, more dynamic assessments of disease burden and infliximab clearance to develop an innovative dosing strategy and improve patient outcomes with anti-TNF therapies.

项目总结