PBPK prediction of ontogeny mediated alteration in hepatic drug elimination

个体发育介导的肝脏药物消除改变的 PBPK 预测

• 批准号: 10012580
• 负责人: Bhagwat Prasad
• 金额: $ 29.71万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2021-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012580
• 关键词: Address; Adolescence; Adolescent; Adult; Age; Body Surface Area; Body Weight; Cell Line; Child; Child Health; Childhood; Cholesterol 7-alpha-Monooxygenase; Clinic; Clinical Data; Clinical Pharmacology; Clinical Trials; Computer Simulation; Data; Development; Dose; Drug Interactions; Drug Kinetics; Drug Modelings; Drug Prescriptions; Drug Transport; Drug toxicity; Drug usage; Enzymes; Ethics; Funding; Future; Genetic Polymorphism; Growth; Hepatic; Hepatocyte; Human; Immunoblotting; In Vitro; Individual; Infant; Intestines; Kidney; Kinetics; Knowledge; Legal; Life; Liver; Liver Microsomes; Logistics; Mediating; Metabolic; Metabolism; Methods; Modeling; Organ; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacogenetics; Phase; Physiological; Population; Proteins; Proteomics; Recombinants; Regimen; Risk; Role; Safety; Statutes and Laws; System; Testing; Tissues; Translating; Vulnerable Populations; Western Blotting; Xenobiotics; age group; age related; base; drug development; drug disposition; drug efficacy; drug metabolism; in vivo; interest; liver metabolism; model design; multiple reaction monitoring; named group; neonate; novel; patient population; pediatric patients; pharmacokinetic model; physiologically based pharmacokinetics; population based; protein expression; public health relevance; safety study; scale up; tool

 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).

 描述（由适用提供）：关于药物处置，儿童（尤其是新生儿和婴儿）与成年人不同。因此，根据成人剂量的经验缩放（例如，基于体重），为该特殊人群选择给药方案是不合适的。由于后勤，道德，安全和法律问题，因此并非总是有可能在诊所建立药物的安全性和有效性，因此这个问题变得更加重要。例如，在1997 - 2010年之间，在399种针对新生儿/婴儿的处方药中，仅研究了28种药物以进行安全性和/或有效性。这是必须开发出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依赖年龄的生理参数与药物特异性参数（例如，体外酶/转运动力学数据）相结合，以开发基于儿科生理的药代动力学（PPBPK）模型。一旦得到验证，可以将这种完全机械的PPBPK模型推广到任何药物中。但是，开发这种儿童模型的最大障碍是缺乏与药物处置有关的蛋白质的绝对个体发育数据，即药物代谢酶（DME）和转运蛋白。众所周知，发展模式存在于主要肝DME的表达中，但是对于大多数DME/Transorters而言，可用的数据要么是定性/半定量性或完全缺少的。因此，作为纠正这一知识差距的第一步，我们建议在我们独特的儿科肝中量化DME和转运蛋白的肝表达（n = 220），并将其与成年人进行比较。我们将使用选择性和鲁棒的多重反应监测（MRM）蛋白质组学方法来量化这些蛋白质。一旦获得了年龄依赖性蛋白质丰度数据，这些数据就可以与体外动力学和其他发育（生理）信息集成在一起，以构建PPBPK模型。可以使用模型化合物上的可用临床数据对这种合理设计的模型进行验证，然后将其推广到肝脏中这些机制消除的药物。由于机械PBPK模型可以描述单个代谢/转运途径在药物处置中的分数作用，因此这种机械工具还能够准确预测这些途径介导的药物 - 药物相互作用（DDIS）和药物遗传学变异性。因此，该提案探讨了新生儿对青少年的肝药物处置的机制。在这项研究中生成的PPBPK模型在儿童健康方面将具有巨大的价值，因为这些对于评估与儿童（包括新生儿/婴儿）首次使用药物（或其他异生物学）相关的风险很重要。