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).

 说明（申请人提供）：就药物配置而言，儿童（尤其是新生儿和婴儿）与成人不同，因此基于经验模型（例如基于体重）为这一特殊人群选择给药方案是不合适的。 ）的成人剂量变得更加重要，因为由于后勤、伦理、安全和医疗法律方面的考虑，并不总是能够在诊所确定药物的安全性和有效性。例如，在 399 种药物中。 1997 年至 2010 年间，仅对 28 种药物的安全性和/或有效性进行了研究，因此，必须开发新的替代方法来预测儿童安全有效的给药方案。年龄依赖性生理参数与药物特定参数（例如，体外酶/转运动力学数据），以开发基于儿科生理学的药代动力学（pPBPK）模型，一旦经过验证，就可以得到充分验证。机制 pPBPK 模型可以推广到任何药物，然而，为儿童开发此类模型的最大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。众所周知，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。为了弥补这一知识差距，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，并将这种表达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。一旦获得了年龄依赖性蛋白质丰度数据，就可以将这些数据与体外动力学和其他发育（生理）信息相结合，以构建 pPBPK 模型，并可以使用可用的方法来验证这种合理设计的模型。模型化合物的临床数据，然后推广到通过这些机制在肝脏中消除的药物，因为机制 pPBPK 模型可以描述个体代谢/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）和这些途径介导的药物遗传变异因此，本研究中生成的 pPBPK 模型将解决新生儿和青少年肝脏药物处置的机制。对于儿童健康而言，这些对于评估儿童（包括新生儿/婴儿，个体发育最重要）首次使用药物（或其他外源性物质）相关的风险非常重要。