Advancing knowledge and developping mechanistic quantitative tools for in vitro-in vivo extrapolations in pharmacokinetics and toxicokinetics

增进知识并开发药代动力学和毒代动力学体外体内外推的机械定量工具

• 批准号: RGPIN-2020-05251
• 负责人: Haddad, Sami
• 金额: $ 2.91万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739861
• 关键词: Advancing; knowledge; developping; mechanistic; quantitative

Physiologically based (PB) pharmacokinetic (PK) or toxicokinetic (TK) modeling is increasingly being used in pharmacology and toxicology, whether it be in drug discovery and development or in regulatory toxicology for environmental and occupational health. When well calibrated and validated, PBPK/TK models allows diverse types of extrapolations that are essential for assessing toxicological and therapeutic impacts of exposures to xenobiotics. More and more efforts are being exerted to increase the capabilities of generic models to quantitatively predict the absorption, the distribution, the metabolism and the excretion of diverse xenobiotics uniquely on the basis of molecular structure and in vitro information. The proposed program aims to contribute to the development of generic PBPK/ TK models and their predictive capabilities by developing in vitro-in vivo extrapolation (IVIVE) approaches by tackling the 3 important issues in PK/TK to better predict internal dosimetry and the relation between external and internal doses : i) the prediction of hepatic clearance of xenobiotics that are highly bound to plasma proteins; (ii) the prediction of renal clearance of albumin-bound xenobiotics as well as for volatile organic chemicals; and (iii) prediction of inhalation absorption and exhalation of polar volatile organic chemicals with high affinity to mucus in the respiratory tract. The program will generate in vitro data for xenobiotics for the mentioned processes, calibrate and validate IVIVE models to in vivo data from rats, or humans when possible, obtained experimentally or from literature. The results of such a research program will greatly enhance our knowledge on how in vitro PK/TK data relate to the pharmacokinetics of xenobiotics in the whole body and in the overall population and will facilitate and speedup the PBPK/ TK modeling process. The development of such mechanistic tools for IVIVE will lead to improvements in health risk assessment practices and dosimetry in the fields toxicology and pharmacology. With this program, Canadian research will continue to be at the forefront of the field of IVIVE in PBPK modeling.

无论是在药物发现和开发中还是用于环境和职业健康的监管毒理学，都越来越多地用于药理学和毒理学中，以生理基础（PB）药代动力学（PK）或有毒动力学（TK）建模越来越多地使用。当经过良好的校准和验证时，PBPK/TK模型允许使用多种类型的外推，这些外推对于评估对异生物生物的暴露的毒理学和治疗影响至关重要。越来越多的努力正在努力提高通用模型的能力，以定量预测在分子结构和体外信息的基础上，独特的多种异种生物学的吸收，分布，代谢和排泄。该计划的计划旨在通过解决PK/ TK中的3个重要问题来更好地预测外部剂量和内部剂量之间的预测，从而更好地预测Xenobiots的预测，从而更好地预测了Xenobiots的预测，从而更好地预测Xenobiotics的预测，从而更好地预测了Xenobiots的预测，从而更好地预测了Xenobiots的预测，从而更好地预测了Xenobiots的预测，从而更好地预测了Xenobiots的预测，从而可以： （ii）预测白蛋白结合的异种生物和挥发性有机化学物质的肾脏清除率； （iii）预测吸入吸收和呼吸具有高亲和力的极性挥发性有机化学物质对呼吸道中的粘液。该程序将为上述过程，校准和验证Ivive模型的异种生物学生成体外数据，以从大鼠或人类的情况下进行体内数据，或者从实验或文献中获得。这样的研究计划的结果将大大增强我们对全体和总体异生物学药物的体外PK/ TK数据如何相关的知识，并将促进和加速PBPK/ TK建模过程。开发这种用于Ivive的机械工具将改善田间毒理学和药理学的健康风险评估实践和剂量测定。通过此计划，加拿大研究将继续处于PBPK建模中Ivive领域的最前沿。