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

生理学(PB)药代动力学(PK)或毒代动力学(TK)建模越来越多地被用于药理学和毒理学，无论是在药物发现和开发中，还是在环境和职业健康的调节毒理学中。当经过良好的校准和验证时，PBPK/TK模型允许进行各种类型的外推，这对于评估暴露于外源物质的毒理学和治疗影响是必不可少的。越来越多的人正在努力提高通用模型的能力，以便根据分子结构和体外信息唯一地定量预测各种外来生物的吸收、分布、代谢和排泄。该计划旨在通过开发体外-体内外推(IVE)方法来促进通用PBPK/TK模型及其预测能力的发展，通过解决PK/TK中的三个重要问题来更好地预测内剂量学以及内外剂量之间的关系：i)预测与血浆蛋白高度结合的外来物的肝清除；(Ii)预测白蛋白结合的外来物以及挥发性有机化合物的肾清除；以及(Iii)预测对呼吸道粘液具有高亲和力的极性挥发性有机物的吸入吸收和呼出。该计划将为上述过程产生外源生物的体外数据，校准和验证IVE模型，如果可能，从实验或从文献中获得的大鼠或人类的体内数据。这一研究计划的结果将极大地增强我们对体外PK/TK数据如何与外源药物在全身和整个人群中的药代动力学相关的知识，并将促进和加速PBPK/TK建模过程。IVE的这种机械化工具的开发将导致改进毒理学和药理学领域的健康风险评估做法和剂量测定。有了这一计划，加拿大的研究将继续走在PBPK建模IVE领域的前沿。

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.