A Systems Pharmacology approach to predict the effects of pregnancy and infectious diseases on transporter-mediated drug disposition

预测妊娠和传染病对转运蛋白介导的药物处置影响的系统药理学方法

• 批准号: 10406307
• 负责人: VERA LUCIA LANCHOTE
• 金额: $ 43.59万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-17 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406307
• 关键词: ABCG2 gene; Address; Affect; Animals; Brazil; CYP3A4 gene; Cells; Clinical; Collaborations; Communicable Diseases; Confidence Intervals; Cytochrome P450; Data; Digoxin; Disease; Dose; Drug Kinetics; Drug Transport; Drug usage; Enterocytes; Enzymes; Epithelial Cells; Estradiol; Funding; Furosemide; Gestational Age; Goals; HIV; Hepatocyte; Hormones; Human; Human Cell Line; In Vitro; Indinavir; Individual; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-6; Intestines; Kidney; Knowledge; Lamivudine; Liver; Logistics; Measures; Mediating; Membrane; Messenger RNA; Methods; POU2F2 gene; Pharmaceutical Preparations; Pharmacology; Plasma; Population; Pregnancy; Pregnant Women; Progesterone; Proteins; Proteomics; Regimen; Reporting; Request for Applications; Safety; System; TNF gene; Tenofovir; Translating; United States National Institutes of Health; Vesicle; Virus Diseases; absorption; clinically significant; cytokine; design; drug clearance; drug disposition; falls; fexofenadine; human tissue; in vivo; interest; men; models and simulation; pharmacokinetic model; physiologically based pharmacokinetics; predictive modeling; rational design; renal epithelium; rosuvastatin

SUMMARY Pregnancy and inflammation (due to infectious diseases) are each known to alter drug pharmacokinetics (PK) by changing the expression and activity of transporters and/or drug-metabolizing enzymes (e.g. CYPs). Quantifying changes in drug PK caused by pregnancy and/or cytokines (elevated during inflammation) is important for rational design of dosing regimens of drugs for pregnant women with infectious diseases. While changes in the PK of CYP-cleared drugs by pregnancy and cytokines have been well-delineated using CYP probe drugs, such data are sorely missing for transporters. However, obtaining data of changes in drug PK by pregnancy and/or pro-inflammatory infectious diseases for every possible transported drug administered to pregnant women (with or without infection) is logistically impossible. Therefore, alternative approaches that can generalize across drugs, transporters and pro-inflammatory infectious diseases are urgently needed. These approaches should accurately predict the alteration in in vivo activity of transporters by pregnancy and pro-inflammatory cytokines. In this proposal, we propose a systems pharmacology approach to predict the effects of pregnancy and/or pro-inflammatory infectious diseases on transporter-mediated drug PK. Our hypothesis is that the magnitude of change in drug PK by pregnancy and/or cytokines can be predicted through clinical PK studies using probe drugs and in vitro experimental data as well as Physiologically Based Pharmacokinetic (PBPK) modeling and simulation (M&S). While probe drugs can yield clinically significant and valuable data, transporter probe drugs, unlike CYP probe drugs, have the limitations that they are not selective. Therefore, to overcome this limitation, we propose a two-pronged approach which utilizes both primary human cells (e.g. hepatocytes, renal epithelial cells, intestinal enterocytes) and transfected cells expressing individual transporters of interest. Using quantitative targeted proteomics, the human cells will allow us to determine the effect of pregnancy hormones or cytokines, on the expression of transporters in these cells. The transporter- transfected cell studies will allow us to determine the intrinsic transport clearance of a drug by a single transporter per pmol of a transporter. Combined, these data will allow us to predict, through PBPK M&S, transporter-mediated clearance of drugs in pregnant women with and without infection. These studies will address a critical gap in our understanding of the effects of pregnancy and/or pro-inflammatory infectious diseases on transporter-mediated drug disposition. Since our approach can be applied to other drugs and other inflammatory diseases, its significance goes well beyond the drugs and inflammatory diseases investigated here. We would like this application to be considered under the NIH-FAPESP initiative (NOT-TW- 16-001). Under this initiative, the clinical PK studies will be conducted in pregnant women with infectious diseases in Brazil, and the clinical PK data obtained will be used to verify our PBPK model predictions.

概括 众所周知，怀孕和炎症（由于传染病）都会通过以下方式改变药物药代动力学 (PK)： 改变转运蛋白和/或药物代谢酶（例如 CYP）的表达和活性。量化 怀孕和/或细胞因子（炎症期间升高）引起的药物 PK 变化对于 合理设计感染性疾病孕妇用药方案。虽然变化 使用 CYP 探针药物已很好地描述了妊娠和细胞因子的 CYP 清除药物的 PK，例如 对于运输商来说，数据严重缺失。然而，通过怀孕和/或获得药物 PK 变化的数据 促炎性传染病对于孕妇服用的每种可能的运输药物（含 或没有感染）在逻辑上是不可能的。因此，可以泛化的替代方法 迫切需要药物、转运蛋白和促炎性传染病。这些方法应该 准确预测妊娠和促炎细胞因子对转运蛋白体内活性的改变。 在本提案中，我们提出了一种系统药理学方法来预测妊娠和/或 促炎性传染病对转运蛋白介导的药物PK。我们的假设是 通过临床 PK 研究可以预测妊娠和/或细胞因子引起的药物 PK 变化幅度 使用探针药物和体外实验数据以及基于生理的药代动力学（PBPK） 建模和模拟（M&S）。虽然探针药物可以产生具有临床意义和有价值的数据，但转运蛋白 与 CYP 探针药物不同，探针药物具有非选择性的局限性。因此，要克服 为了克服这一限制，我们提出了一种双管齐下的方法，利用两种原代人类细胞（例如 肝细胞、肾上皮细胞、肠上皮细胞）和表达个体的转染细胞 感兴趣的转运蛋白。使用定量靶向蛋白质组学，人类细胞将使我们能够确定 妊娠激素或细胞因子对这些细胞中转运蛋白表达的影响。运输者—— 转染细胞研究将使我们能够确定单一药物的内在转运清除率 每 pmol 转运蛋白的转运蛋白。综合起来，这些数据将使我们能够通过 PBPK M&S 进行预测， 有或没有感染的孕妇中转运蛋白介导的药物清除。这些研究将 解决我们对怀孕和/或促炎症影响的理解中的一个关键差距 传染病对转运蛋白介导的药物处置的影响。由于我们的方法可以应用于其他 药物与其他炎症性疾病，其意义远远超出药物与炎症性疾病 在这里进行了调查。我们希望根据 NIH-FAPESP 倡议（NOT-TW- 16-001）。根据该倡议，临床药代动力学研究将在感染传染性的孕妇中进行。 巴西的疾病，获得的临床 PK 数据将用于验证我们的 PBPK 模型预测。