Physiologically-based pharmacokinetic modelling

Physiologically-based pharmacokinetic modeling (PBPK) is a mathematical modeling technique for prediction of the absorption, distribution, metabolization and excretion (ADME) of a compound in humans and other animal species. PBPK modeling is used in pharmaceutical research and development, and risk assessment from industrial and environmental chemical exposure.

PBPK models strive to be mechanistic by mathematically transcribing anatomical, physiological, physical, and chemical descriptions of the phenomena involved in the complex ADME processes. Some degree of residual simplification and empiricism is still present in those models, but they have an extended domain of applicability compared to that of classical, empirical function based, pharmacokinetic models. Given that property, PBPK models may have purely predictive use, but other uses, such as statistical inference, have been made possible by the development of Bayesian statistical tools able to deal with complex models. That is true for both toxicity risk assessment and therapeutic drug development.

PBPK models try to rely "a priori" on the anatomical and physiological structure of the body. These are usually also multi-compartment models, but the compartments correspond to predefined organs or tissues, for which the interconnections correspond to blood or lymph flows (more rarely to diffusions). A system of differential equations can still be written, but its parameters represent blood flows, pulmonary ventilation rate, organ volumes etc., for which information is available in scientific publications. Indeed the description of the body is simplified and a balance needs to be struck between complexity and simplicity. Besides the advantage of allowing the recruitment of "a priori" information about parameter values, these models also facilitate inter-species transpositions or extrapolation from one mode of administration to another ("e.g.", inhalation to oral). An example of a 7-compartment PBTK model, suitable to describe the fate of many solvents in the mammalian body, is given in the next Figure.

Bibliography

*Bouvier d’Yvoire M., Prieto P., Blaauboer B.J., Bois F., Boobis A., Brochot C., Coecke S., Freidig A., Gundert-Remy U., Hartung T., Jacobs M. N., Lavé T., Leahy D.E., Lennernäs H., Loizou G.D., Meek B., Pease C., Rowland M., Spendiff M., Yang J., Zeilmaker M. (2007) "Physiologically-based kinetic modelling (PBK modelling): meeting the 3Rs agenda - The report and recommendations of ECVAM Workshop 63a", Alternatives to Laboratory Animals, 35:661–671.
*Loizou G., Spendiff M., Barton H.A. , Bessems J., Bois F., Bouvier d’Yvoire M., Buist H., Clewell H.J.III, Meek B., Gundert-Remy U., Goerlitz G., Schmitt W. (2008) "Development of good modelling practice for physiologically based pharmacokinetic models for use in risk assessment: the first steps", Regulatory Toxicology and Pharmacology, 50:400-411.
*Reddy, M. "et al." (2005) "Physiologically Based Pharmacokinetic Modeling : Science and Applications", Wiley-Interscience.

Forums

* [http://www.pbpk.org pbpk.org]

oftware

* [http://www.acslx.com/Pharma.asp acslXtreme software for PBPK modeling]
*Simcyp Simulator [http://www.simcyp.com Simcyp - Population-based pharmacokinetic modelling and simulation]
* [http://www.pk-sim.com PK-Sim - Physiologically based pharmacokinetic modelling and simulation]
* [http://q-pharm.com/products_services/pharmacokinetic_modeling Quantum - Pharmacokinetic modelling ]
*Simulations Plus - [http://www.simulations-plus.com/Products.aspx?grpID=3&cID=16&pID=11 GastroPlus]
*MCSim: [http://www.gnu.org/software/mcsim "MCSim - Free simulation software"]