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

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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.