Application of Physiologically-Based Pharmacokinetic Modeling to Characterize Drug-Drug Interactions in Infants

应用基于生理学的药代动力学模型来表征婴儿药物相互作用

基本信息

批准号：
10399613
负责人：
Daniel Gonzalez
金额：
$ 49.16万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10399613
关键词：
2 year old Adult Advocate Affect Age CYP2C9 gene CYP3A4 gene Childhood Clinical Pharmacology Clinical Trials Collection Data Data Collection Dependence Doctor of Pharmacy Doctor of Philosophy Dose Drug Addiction Drug Combinations Drug Interactions Drug Kinetics Drug Metabolism Inhibition Drug Modelings Enrollment Environment Enzymes Ethics Evaluation Fellowship Fentanyl Fluconazole Goals Infant Infrastructure Intervention Knowledge Lead Life Light Logistics Mediating Medical Metabolism Midazolam National Institute of Child Health and Human Development Patients Pharmaceutical Preparations Phenobarbital Phenytoin Physiological Postdoctoral Fellow Principal Investigator Public Health Recommendation Recording of previous events Regimen Research Risk Science Toxic effect Training Valproic Acid base cytochrome P450 3A dosage drug development drug metabolism fosphenytoin inhibitor pediatric drug development pharmacokinetic model predictive modeling prospective skills standard of care tool unethical volunteer

项目摘要

ABSTRACT Dedicated pharmacokinetic (PK) drug-drug interaction (DDI) studies are performed in healthy adult volunteers during drug development. However, dedicated PK DDI studies are rarely performed in infants due to ethical and logistical reasons. This results in the extrapolation of adult drug dosing recommendations that account for the DDI potential to infants despite known age-induced physiological changes that can alter PK and affect the DDI magnitude in infants. Physiologically-based pharmacokinetic (PBPK) models are an ideal tool to characterize PK DDIs in infants because they can account for the DDI mechanism and physiological age-induced changes that affect the DDI magnitude early in life. This proposal will evaluate a systematic approach to PK DDI evaluation in infants using PBPK modeling and real-world data to accelerate the availability of age-appropriate drug dosing recommendations in light of the DDI potential. We will characterize DDIs involving the cytochrome P450 (CYP) 3A substrates midazolam and fentanyl, and the CYP2C9/2C19 substrate phenobarbital, when co-administered with drugs that inhibit their metabolism. We will validate the PBPK model DDI predictions using real-world data collected from infants receiving the drug combinations per standard of care. The PBPK models will then guide drug dosing that accounts for differences in DDI magnitude with age. Once our systematic approach to PBPK model informed DDI evaluation in infants is established, it can be applied to characterize other PK DDIs and accelerate the availability of drug dosing recommendations for infants in light of the DDI potential.

抽象的在健康成年志愿者中进行专门的药代动力学 (PK) 药物相互作用 (DDI) 研究在药物开发过程中。然而，由于伦理和道德问题，专门的 PK DDI 研究很少在婴儿中进行。后勤原因。这导致了成人药物剂量建议的外推，该建议考虑了尽管已知年龄引起的生理变化会改变 PK 并影响 DDI，但 DDI 对婴儿仍有潜力婴儿的大小。基于生理学的药代动力学 (PBPK) 模型是表征 PK 的理想工具婴儿 DDI，因为它们可以解释 DDI 机制和生理年龄引起的变化，影响生命早期的 DDI 大小。该提案将评估 PK DDI 评估的系统方法婴儿使用 PBPK 模型和真实世界数据来加速获得适合年龄的药物剂量根据 DDI 潜力提出建议。我们将表征涉及细胞色素 P450 (CYP) 的 DDI 共同给药时，3A 底物咪达唑仑和芬太尼以及 CYP2C9/2C19 底物苯巴比妥使用抑制其新陈代谢的药物。我们将使用真实世界数据验证 PBPK 模型 DDI 预测从按照护理标准接受药物组合的婴儿收集。 PBPK 模型将指导解释 DDI 大小随年龄变化的药物剂量。一旦我们采用系统化的 PBPK 方法建立了婴儿 DDI 评估模型，可用于表征其他 PK DDI 和鉴于 DDI 的潜力，加快提供婴儿药物剂量建议。