PBPK prediction of ontogeny mediated alteration in hepatic drug elimination

 描述（申请人提供）：儿童（尤其是新生儿和婴儿）的药物处置与成人不同。因此，不适合根据经验比例（例如，基于体重）的成人剂量。由于后勤、伦理、安全和医学法律的问题，在临床上并不总是能够确定药物在儿童中的安全性和有效性，因此这个问题变得更加重要。例如，在1997年至2010年期间为新生儿/婴儿开具的399种药物中，仅对28种药物的安全性和/或有效性进行了研究。因此，迫切需要开发新的替代方法来预测儿童安全有效的给药方案。一种这样的方法是将年龄依赖性生理参数与药物特异性参数（例如，体外酶/转运动力学数据）以开发儿科生理学药代动力学（pPBPK）模型。一旦得到验证，这种完全机械的pPBPK模型可以推广到任何药物。然而，在开发用于儿童的此类模型中最大的障碍是缺乏与药物处置相关的蛋白质（即药物代谢酶（DME）和转运蛋白）的绝对个体发育数据。已知主要肝脏DME的表达存在发育模式，但大多数DME/转运蛋白的可用数据要么是定性/半定量的，要么完全缺失。因此，作为纠正这一知识差距的第一步，我们建议量化我们独特的儿科肝脏（n=220）中DME和转运蛋白的肝脏表达，并将其与成人的表达进行比较。我们将使用选择性和强大的多反应监测（MRM）蛋白质组学方法来定量这些蛋白质。一旦年龄依赖性蛋白质丰度数据可用，这些数据可以与体外动力学和其他发育（生理）信息整合以构建pPBPK模型。这种合理设计的模型可以使用模型化合物的可用临床数据进行验证，然后推广到通过这些机制在肝脏中消除的药物。由于机制pPBPK模型可以描绘个别代谢/转运途径在药物处置中的部分作用，因此这种机制工具也能够准确预测药物-药物相互作用（DDI）和由这些途径介导的药物遗传学变异性。因此，本提案讨论了新生儿至青少年的肝脏药物处置机制。本研究中生成的pPBPK模型将对儿童健康具有巨大价值，因为这些模型对于评估儿童（包括新生儿/婴儿，其中个体发育最重要）首次使用药物（或其他外源性生物素）相关的风险非常重要。

 DESCRIPTION (provided by applicant): With respect to drug disposition, children (especially neonates and infants) are different than the adults. Therefore it is not appropriate to select dosing regimen for this special population based on empirical scaling (e.g., based on body weight) of the adult dose. This issue becomes more significant as it is not always possible to establish safety and efficacy of drugs in the children at clinic due to logistical, ethical, safetyand medico- legal concerns. For instance, out of 399 prescribed drugs to neonates/infants between 1997-2010, only 28 drugs were studied for the safety and/or efficacy. Thus, it is imperative that novel alternative approaches are developed to predict safe and efficacious dosing regimens for children. One such approach is to integrate age- dependent physiological parameters with drug specific parameters (e.g., in vitro enzyme/transport kinetic data) to develop a pediatric physiologically based pharmacokinetic (pPBPK) model. Once validated, such fully mechanistic pPBPK model can be generalized for any drug. However, the biggest hurdle in developing such models for children are the lack of absolute ontogeny data on the proteins that are related to drug disposition, i.e,, drug metabolizing enzymes (DMEs) and transporters. It is known that developmental pattern exists in the expression of major hepatic DMEs, but the available data are either qualitative/semi-quantitative or completely missing for most of the DMEs/transporters. Therefore, as a first step towards rectifying this gap in knowledge we propose to quantify the hepatic expression of DMEs and transporters in our unique pediatric livers (n=220) and compare this expression with that in adults. We will use selective and robust multiple reaction monitoring (MRM) proteomic approach to quantify these proteins. Once the age-dependent protein abundance data are available, these data can be integrated with in vitro kinetics and other developmental (physiological) information to construct a pPBPK models. Such rationally designed models can be validated using available clinical data on the model compounds, and then generalized to drugs that are eliminated by these mechanisms in the liver. Because mechanistic pPBPK models can delineate fractional role of individual metabolic/transport pathways in drug disposition, such mechanistic tools are also capable of accurately predicting drug-drug interactions (DDIs) and pharmacogenetic variability mediated by these pathways. Hence, this proposal addresses the mechanisms of hepatic drug disposition in neonates to adolescents. The pPBPK model generated in this study will be of enormous value with respect to child health as these will be important to assess the risk associated with the first use of drug (or other xenobiotics) in children (including neonates/infants, where the ontogeny matters most).