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

摘要 在健康成人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，由于伦理和环境因素，很少在婴儿中进行专门的PK DDI研究。 后勤原因。这导致了对成人药物剂量建议的外推， 尽管已知年龄诱导的生理变化可改变PK并影响DDI，但仍存在对婴儿的DDI潜力 在婴儿中的重要性。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机制和生理年龄诱导的变化， 影响生命早期DDI的大小。本提案将评价PK DDI评价的系统方法， 使用PBPK建模和真实世界数据的婴儿，以加速提供适合年龄的药物剂量 根据DDI的潜力提出建议。我们将描述涉及细胞色素P450（CYP）的DDI。 3A底物咪达唑仑和芬太尼，以及CYP 2C 9/2C 19底物苯巴比妥（当联合给药时） 用药物抑制他们的新陈代谢我们将使用真实数据验证PBPK模型DDI预测 从接受药物组合的婴儿中收集。然后，PBPK模型将指导 药物剂量，说明DDI幅度随年龄的差异。一旦我们对PBPK的系统方法 建立了婴儿DDI评价模型，可用于表征其他PK DDI， 根据DDI的可能性，加快提供婴儿药物剂量建议。

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.