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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.

总结