The role of CYP3A7 in the disposition and Toxicity of HIV inhibitors in the developing infant

CYP3A7 在 HIV 抑制剂对发育中婴儿的处置和毒性中的作用

• 批准号: 10012258
• 负责人: Jed Noah Lampe
• 金额: $ 41.26万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012258
• 关键词: Achievement; Active Sites; Adult; Affect; Affinity; Amino Acids; CYP3A4 gene; Crystallization; Cytochrome P450; Data; Development; Drug Interactions; Drug Kinetics; Drug Metabolism Inhibition; Drug Monitoring; Drug Prescriptions; Drug toxicity; Drug usage; Enzymes; Fostering; Gestational Age; Goals; HIV; Health; Hepatotoxicity; Human; In Vitro; Infant; Knowledge; Lead; Life; Ligands; Liver; Liver Microsomes; Lopinavir; Mediating; Metabolic; Metabolism; Modeling; Nelfinavir; Nevirapine; Pharmaceutical Preparations; Physiological; Population; Premature Infant; Production; Proteins; Public Health; Publishing; Recombinants; Reporting; Research; Ritonavir; Roentgen Rays; Role; Safety; Site; Structure; Testing; Therapeutic; Toxic effect; United States National Institutes of Health; Vulnerable Populations; X-Ray Crystallography; base; clinically relevant; drug clearance; drug disposition; drug efficacy; drug metabolism; efavirenz; enzyme structure; functional group; improved; improved outcome; inhibitor/antagonist; innovation; medication safety; metabolic profile; neonatal infection; neonate; novel; novel therapeutics; pediatric patients; pharmacokinetic model; physiologically based pharmacokinetics; preclinical development; safety testing; success

ABSTRACT Each year sick and premature infants infected with HIV are treated with a variety of drugs, despite the fact that these drugs have never been tested for safety and efficacy in this vulnerable population. A primary determinant for the pharmacokinetic (PK) and hepatotoxicity profile of many of these drugs is cytochrome P450 metabolism. CYP3A7 is the predominant P450 enzyme in the in the developing infant (≤6 mos. Post- Gestational Age). Recently published reports and our own preliminary results have demonstrated that CYP3A7 can produce a metabolic profile significantly different than that of adult CYP3A4. These differences in metabolism can alter the PK parameters and safety profiles of many HIV drugs used in pediatric patients, leading to reduced efficacy or increased toxicity. Therefore, there exists a critical need to determine the PK and metabolic profiles of clinically relevant CYP3A7 HIV drug substrates to the improve safety and efficacy of these drugs in infants. The objective of this proposal is to determine the functional consequences and mechanistic basis of the differences in HIV drug metabolism between CYP3A7 and adult CYP3A4. Our specific hypothesis is that the differences in HIV drug metabolism are due to changes in enzyme structure which lead to substantial alterations in drug clearance, drug-drug interactions, and production of reactive metabolites. Our first aim is to develop a physiologically based PK (PBPK) model for the disposition of four commonly prescribed HIV inhibitors: ritonavir, lopinavir, nevirapine, and efavirenz. To achieve this, we will monitor drug metabolism and identify metabolites in vitro with both recombinant CYP3A7 and CYP3A4 enzymes and human liver microsomes (HLMs) from the adult and the infant at different stages of development. We will utilize the results from these studies to produce predictive PK models for the developing infant. Our second aim is to identify the CYP3A7 inhibitory capacity, potential drug-drug interactions, and reactive metabolites for each of these inhibitors. Finally, our third aim is to define the structural basis of the differences in HIV drug metabolism observed between CYP3A7 and CYP3A4. To do this, we propose to obtain an X-ray crystal structure for CYP3A7 with the substrates ritonavir and nevirapine, and perform Saturation Transfer Difference NMR to identify amino acid residues and ligand functional groups that are important for enzyme-ligand interaction. We expect that these studies will allow us to determine how structural differences contribute to the observed metabolic differences. The proposed research is innovative because it seeks to change the current conceptual framework by producing improved infant PBPK models for HIV drug disposition using HLMs, and novel crystal structures for this important enzyme. This research will improve health outcomes by improving our ability to accurately predict pharmacokinetics and drug-drug interactions of some important HIV drugs prescribed to the developing infant. Additionally, it will positively impact our ability to understand CYP3A7 HIV drug metabolism based on structure, which will be useful in the development of new drugs specifically targeted to infants.

抽象的 每年，感染艾滋病毒的患病婴儿和早产儿都会接受各种药物治疗，尽管 事实上，这些药物从未在这一弱势群体中进行过安全性和有效性测试。 许多此类药物的药代动力学 (PK) 和肝毒性特征的决定因素是细胞色素 P450 CYP3A7 是发育中婴儿（≤6 个月后）的主要 P450 酶。 最近发表的报告和我们自己的初步结果表明 CYP3A7 可以产生与成人 CYP3A4 显着不同的代谢特征。 代谢可以改变儿科患者使用的许多 HIV 药物的 PK 参数和安全性， 导致功效降低或毒性增加因此，迫切需要确定 PK 和 临床相关 CYP3A7 HIV 药物底物的代谢特征，以提高这些药物的安全性和有效性 该提案的目标药物是确定功能性后果和机制。 这是 CYP3A7 和成人 CYP3A4 之间 HIV 药物代谢差异的基础。 HIV药物代谢的差异是由于酶结构的变化导致的 药物清除、药物相互作用和反应性代谢物产生的显着改变。 第一个目标是开发一个基于生理学的 PK (PBPK) 模型，用于处理四种常见的 处方 HIV 抑制剂：利托那韦、洛匹那韦、奈韦拉平和依非韦伦 为了实现这一目标，我们将监测药物。 使用重组 CYP3A7 和 CYP3A4 酶以及人体外代谢并鉴定代谢物 我们将利用来自成人和婴儿不同发育阶段的肝微粒体（HLM）。 我们的第二个目标是根据这些研究的结果为发育中的婴儿建立预测 PK 模型。 确定每种药物的 CYP3A7 抑制能力、潜在的药物相互作用和反应性代谢物 最后，我们的第三个目标是确定 HIV 药物代谢差异的结构基础。 为此，我们建议获得 CYP3A7 和 CYP3A4 之间的 X 射线晶体结构。 CYP3A7 与底物利托那韦和奈韦拉平，并进行饱和转移差核磁共振 识别对酶-配体相互作用重要的氨基酸残基和配体官能团。 期望这些研究将使我们能够确定结构差异如何影响观察到的结果 拟议的研究具有创新性，因为它试图改变当前的概念。 框架，通过使用 HLM 和新型晶体生成改进的婴儿 PBPK 模型来进行 HIV 药物处置 这项重要酶的结构将通过提高我们的能力来改善健康结果。 准确预测一些重要的 HIV 药物的药代动力学和药物相互作用 此外，它将对我们了解 CYP3A7 HIV 药物代谢的能力产生积极影响。 基于结构，这将有助于开发专门针对婴儿的新药。