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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=764599
• 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.

基于生理学 (PB) 的药代动力学 (PK) 或毒代动力学 (TK) 模型越来越多地应用于药理学和毒理学，无论是药物发现和开发还是环境和职业健康的监管毒理学。经过良好校准和验证后，PBPK/TK 模型可以进行多种类型的外推，这对于评估外源性物质暴露的毒理学和治疗影响至关重要。人们越来越多地努力提高通用模型的能力，以基于分子结构和体外信息独特地定量预测不同外源物质的吸收、分布、代谢和排泄。拟议的计划旨在通过开发体外-体内外推（IVIVE）方法，通过解决 PK/TK 中的 3 个重要问题来促进通用 PBPK/TK 模型及其预测能力的开发，以更好地预测内部剂量测定以及外部和内部剂量之间的关系：i）预测与血浆蛋白高度结合的异生物质的肝脏清除率； (ii) 预测与白蛋白结合的异生物质以及挥发性有机化学物质的肾脏清除率； (iii) 预测与呼吸道粘液具有高亲和力的极性挥发性有机化学物质的吸入吸收和呼出。该程序将为上述过程生成异生素的体外数据，根据通过实验或文献获得的大鼠或人类（如果可能）的体内数据来校准和验证 IVIVE 模型。这样的研究计划的结果将极大地增强我们对体外 PK/TK 数据如何与全身和总体人群中异生素的药代动力学相关的了解，并将促进和加速 PBPK/TK 建模过程。 IVIVE 此类机械工具的开发将改善毒理学和药理学领域的健康风险评估实践和剂量测定。通过该计划，加拿大研究将继续处于 IVIVE PBPK 建模领域的前沿。