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

摘要 在健康成年志愿者中进行专门的药代动力学(PK)药物-药物相互作用(DDI)研究 在药物研发过程中。然而，专门的PK DDI研究很少在婴儿中进行，因为伦理和 后勤方面的原因。这导致了成人给药建议的推断，这解释了 婴儿的DDI潜力，尽管已知的年龄诱导的生理变化可以改变PK并影响DDI 婴儿中的大小。基于生理的药代动力学(PBPK)模型是描述PK的理想工具 婴儿中的DDS，因为它们可以解释DDI的机制和生理年龄诱导的变化 在生命早期影响DDI的大小。该提案将评估#年PK DDI评估的系统方法 婴儿使用PBPK模型和真实世界数据加速获得适合年龄的药物剂量 根据DDI潜力提出建议。我们将描述涉及细胞色素P450(CyP)的DDIS 3A底物咪达唑仑和芬太尼，以及CYP2C9/2C19底物苯巴比妥联合给药时 使用抑制他们新陈代谢的药物。我们将使用真实世界的数据验证PBPK模型DDI预测 根据护理标准从接受药物组合的婴儿中收集。然后，PBPK模型将指导 用药剂量解释了DDI大小随年龄的不同。一旦我们对PBPK采取系统的方法 本研究建立了婴幼儿DDI评估模型，该模型可应用于其他PK、DDis的特征化 根据DDI潜力，加快提供婴儿用药建议。

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.