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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

基本信息

批准号：
10617748
负责人：
VERA LUCIA LANCHOTE
金额：
$ 55.37万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10617748
关键词：
ABCG2 gene Address Affect Animals Avena sativa Brazil CYP3A4 gene Cells Clinical Collaborations Communicable Diseases Confidence Intervals Cytochrome P450 Data Digoxin Disease Dose Drug Kinetics Drug Transport Drug usage Eligibility Determination 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 Measures Mediating Membrane Messenger RNA Methods Pharmaceutical Preparations Pharmacology Plasma Population Pregnancy Pregnant Women Progesterone Proteins Proteomics Regimen Reporting Request for Applications Safety System TNF gene Tenofovir Therapeutic Transfection Translating United States National Institutes of Health Vesicle Virus Diseases Woman 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

项目摘要

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.

摘要怀孕和炎症(由传染病引起)均可通过以下途径改变药物的药代动力学(PK) 改变转运蛋白和/或药物代谢酶(如细胞色素P450)的表达和活性。量化妊娠和/或细胞因子(在炎症期间升高)引起的药物PK变化对妊娠合并传染病患者合理用药方案的设计。虽然在通过妊娠和细胞因子清除的CYP药物的PK已经被用CYP探针药物很好地描绘出来，例如运输商严重缺乏数据。然而，获得怀孕和/或药物PK变化的数据对孕妇使用的每种可能的运输药物的促炎性传染病(与或者没有感染)在逻辑上是不可能的。因此，其他方法可以推广到迫切需要药物、转运体和促炎性传染病。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影响。在这项建议中，我们提出了一种系统药理学方法来预测怀孕和/或促炎性传染病对转运蛋白介导的药物PK的影响。我们的假设是通过临床PK研究可以预测药物PK因妊娠和/或细胞因子的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) 建模与仿真(M&S)。虽然探测药物可以产生临床上有意义和有价值的数据，但Transporter 与CYP探针药物不同，探测药物具有非选择性的局限性。因此，要克服为了克服这一局限，我们提出了一种双管齐下的方法，即利用两个原代人类细胞(例如，肝细胞、肾上皮细胞、肠上皮细胞)和表达个体的转基因细胞感兴趣的运输商。利用定量靶向蛋白质组学，人类细胞将允许我们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。传送者- 转基因细胞研究将使我们能够确定一种药物的内在转运清除传送器的每毫摩尔传送器。综合起来，这些数据将使我们能够通过PBPK M&S预测，转运蛋白介导的药物在感染和未感染孕妇体内的清除。这些研究将解决我们对怀孕和/或促炎的影响的理解上的一个严重差距传染病对转运蛋白介导的药物处置的影响。由于我们方法可以应用于其他药物和其他炎症性疾病，其意义远远超出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(不是TW- 16-001)。在这项倡议下，临床PK研究将在感染了所获得的临床PK数据将用于验证我们的PBPK模型预测。