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.

概括妊娠和炎症（由于传染性疾病）众所周知会改变药物药代动力学（PK）改变转运蛋白和/或药物代谢酶的表达和活性（例如CYPS）。量化妊娠和/或细胞因子引起的药物PK的变化（炎症期间升高）对于用于传染病的孕妇药物药物剂量方案的合理设计。而在变化使用CYP探针药物对妊娠和细胞因子的CYP清除药物的PK进行了很好的限制，例如转运蛋白非常缺少数据。但是，通过怀孕和/或获得药物PK变化的数据针对给孕妇服用的每种可能运输的药物的促炎性传染病（或者没有感染）在逻辑上是不可能的。因此，可以推广的替代方法迫切需要药物，转运蛋白和促炎性传染病。这些方法应该准确地通过怀孕和促炎细胞因子来预测转运蛋白体内活性的改变。在此提案中，我们提出了一种系统药理学方法，以预测怀孕和/或转运蛋白介导的药物PK上的促炎性传染病。我们的假设是可以通过临床PK研究预测药物PK的变化大小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）建模和仿真（M＆S）。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，探针药物的局限性是它们不是选择性的。因此，要克服这一局限性，我们提出了一种使用两种原代人类细胞的两管齐下的方法（例如肝细胞，肾上皮细胞，肠肠上皮细胞）和表达个体的转染细胞感兴趣的运输商。使用定量靶向蛋白质组学，人类细胞将使我们能够确定怀孕激素或细胞因子对这些细胞转运蛋白表达的影响。转运蛋白转染的细胞研究将使我们能够确定单个药物的固有转运清除率转运蛋白的每个PMOL转运蛋白。这些数据结合在一起，使我们能够通过PBPK M＆S预测转运蛋白介导的药物清除有或没有感染的孕妇。这些研究会在我们对怀孕和/或促炎的影响的理解时，要解决一个关键的差距转运蛋白介导的药物处置上的传染病。由于我们的方法可以应用于其他药物和其他炎症性疾病，其意义远远超出了药物和炎症性疾病在这里调查。我们希望根据NIH-FAPESP倡议（NOT-TW-）考虑此应用程序 16-001）。根据该计划，将在具有感染性的孕妇中进行临床PK研究巴西的疾病以及获得的临床PK数据将用于验证我们的PBPK模型预测。