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: 10644297
• 负责人: VERA LUCIA LANCHOTE
• 金额: $ 12.15万
• 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/10644297
• 关键词: Address; Award; Brazil; Cells; Clinical; Communicable Diseases; Data; Disease; Dose; Drug Kinetics; Drug Transport; Enterocytes; Enzymes; Epithelial Cells; Funding; Hepatocyte; Hormones; Human; In Vitro; Individual; Infection; Inflammation; Inflammatory; Intestines; Logistics; Mediating; Parents; Pharmaceutical Preparations; Pharmacology; Pregnancy; Pregnant Women; Proteomics; Regimen; System; United States National Institutes of Health; cytokine; drug clearance; drug disposition; in vivo; interest; models and simulation; physiologically based pharmacokinetics; predictive modeling; rational design; renal epithelium

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, such data are sorely missing for transporters. However, obtaining the latter 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). Transporter probe drugs, unlike CYP probe drugs, have the limitations that they are not selective. To overcome this limitation, we propose a two-pronged approach which utilizes both primary human cells (hepatocytes, renal epithelial cells, and intestinal enterocytes) and transfected cells expressing individual transporters of interest. Using quantitative targeted proteomics, the human cells will allow us to determine the effects 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. Then, the in vitro intrinsic transporter-mediated clearances in primary cells will be extrapolated to in vivo using PBPK M&S. Combined, these data will allow us to predict 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 throughout pregnancy, 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). We are requesting support for only the in vitro studies proposed here as well as PBPK M&S. FAPESP will support the clinical PK studies in pregnant women with infectious diseases in Brazil. The clinical PK data obtained in Brazil will be used to verify our PBPK model predictions.

摘要 怀孕和炎症(由传染病引起)都会改变药物的药代动力学(PK)。 通过改变转运蛋白和/或药物代谢酶(例如，细胞色素P450)的表达和活性。 量化由妊娠和/或细胞因子引起的药物PK的变化(炎症期间升高)是 对合理设计孕妇感染性疾病给药方案具有重要意义。而当 这些数据已经很好地描绘了妊娠和细胞因子对CYP清除药物的PK的影响 对于运输商来说都是非常缺失的。然而，对于每一种可能运输的药物，都要获得后者 对孕妇(感染或不感染)进行管理在后勤上是不可能的。因此，替代方案 可以在药物、转运体和促炎性传染病之间推广的方法是 急需之物。这些方法应该准确地预测体内转运蛋白活性的变化 怀孕和促炎细胞因子。在这项建议中，我们提出了一种系统药理学方法。 预测妊娠和/或炎症性疾病对转运蛋白介导的影响 毒品PK。我们的假设是，怀孕和/或细胞因子对药物PK的变化幅度可能是 通过使用探针药物的临床PK研究和体外实验数据以及 基于生理的药代动力学建模与仿真(M&S)。传输者探测毒品， 与CYP探针药物不同的是，它们具有非选择性的限制。为了克服这一限制，我们 提出一种双管齐下的方法，利用原代人类细胞(肝细胞、肾上皮细胞) 细胞和肠道细胞)和表达单个转运蛋白的转基因细胞。 利用定量靶向蛋白质组学，人类细胞将允许我们确定怀孕的影响 激素或细胞因子对这些细胞中转运蛋白表达的影响。转运蛋白介导的细胞研究 将使我们能够确定一种药物在每毫克摩尔的单一转运体的固有转运清除量 传送器。然后，原代细胞中的体外固有转运体介导的清除将被外推到 在活体中使用PBPK M&S结合，这些数据将使我们能够预测转运体介导的清除 感染和不感染孕妇的药物。这些研究将解决我们在 了解妊娠和/或炎症性传染病对转运蛋白的影响 调解药物处置。由于我们的方法可以应用于其他药物和其他炎症 在整个怀孕期间，它的意义远远超出了药物和炎症性疾病 在这里调查过。我们希望这项申请在NIH-FAPESP倡议下得到考虑 (非-TW-16-001)。我们只要求支持这里提出的体外研究以及PBPK M&S.FAPESP将支持巴西患有传染病的孕妇的临床PK研究。 在巴西获得的临床PK数据将用于验证我们的PBPK模型预测。