Drug PBPK physiologically based

Physiologically Based Toxicokinetic (PBTK) models are derived similarly to Physiologically Based Pharmacokinetic (PBPK) models, which have been used for a number of years in the development of medicinal drugs. They describe the rat or man as a set of tissue compartments, i.e., liver, adipose tissues, poorly perfused tissues, and richly perfused tissues along with a description of metabolism in the liver. In case of volatile organic compounds a description of gas exchange at the level of the lung is included, see also Section 4.3.6. 

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

Physiologically-based pharmacokinetic (PBPK) models have been developed for a number of drugs and chemicals, in order to better understand and simulate the dynamics of those compounds in the body. Advances made to date indicate that valid PBPK models can accurately predict the... 

Bjorkman S. 2005. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling theophylline and midazolam as model drugs. Br J Clin Pharmacol 59 691-704. 

Physiologically based pharmacokinetic (PBPK) models are a special type of PK model that attempts to provide more definition to the model analysis by incorporating physiological factors into the model design, like tissue volumes, blood flow rates, and species-specific enzyme characteristics that can more accurately differentiate the dose-response relationship for a chemical or drug in one species from that of another species. The power of this approach is to be able to perform laboratory studies, both in vitro and in vivo, in common experimental species... 

Many types of modeling techniques are available in the discovery phase of drug development, from structure activity relationships (SAR) to physiology based pharmacokinetics (PBPK) and pharmacokinetics-/pharmacodynamics (PK/PD) to help choosing some of the lead compounds. Some tests that are carried out by discovery include techniques related to structure determination, metabolism, and permeability NMR, MS/MS, elemental analysis, PAMPA, CACO-2, and in vitro metabolic stability. Although they are important as a part of physicochemical molecular characterization under the biopharmaceutics umbrella, they will not be discussed here. The reader can find relevant information in numerous monographs [9,10]. 

Andersen, M.E. (1995) Physiologically-based pharmacokinetic (PBPK) models in the study of the disposition and biological effects of xenobiotics and drugs. Toxicology Letters, 82/83, 341-348. 

Prior to 2002, most studies published on physiologically-based pharmacokinetic models focused on the distribution and elimination of environmental toxins such as dioxin, styrene, and organic solvents [68-70]. PBPK models for drug molecules generally relied on tissue/plasma partition coefficients (Kps) measured in rat [71-73]. 

There is a bioreaction engineering home problem in virtually every chapter. Bio-related web modules include physiological-based-pharmacokinetic (PBPK) models of ethanol metabolism, of drug distribution, and of venomous snake bites by the Russels viper and the cobra. 

Peters,S.A.,Ungell,A.L.,Dolgos,H. (2009) Physiologically based pharmacokinetic (PBPK) modeling and simulation applications in lead optimization. Curr. Opin. Drug Discov. 

Computational modeling is a powerful tool to predict toxicity of drugs and environmental toxins. However, all the in silico models, from the chemical structure-related QSAR method to the systemic PBPK models, would beneht from a second system to improve and validate their predictions. The accuracy of PBPK modeling, for example, depends on precise description of physiological mechanisms and kinetic parameters applied to the model. The PBPK method has primary limitations that it can only predict responses based on assumed mechanisms, without considerations on secondary and unexpected effects. Incomplete understanding of the biological mechanism and inappropriate simplification of the model can easily introduce errors into the PBPK predictions. In addition values of parameters required for the model are often unavailable, especially those for new drugs and environmental toxins. Thus a second validation system is critical to complement computational simulations and to provide a rational basis to improve mathematical models. 

To address the inaccuracy of estimates for volume at steady state (Vss) for strongly basic drug molecules, Rodgers and Rowland have proposed an extension to the tissue composition method that takes into account the volume fraction of acidic phospholipids. Presumably, the higher values of Vss observed for these basic molecules is due to the interaction of the cationic state (at physiological pH) of the base with the anionic state of the acidic phospholipids [82-85], Several commercial software programs are now extensively used in the pharmaceutical industry for PBPK modeling [86, 41, 87, 11]. 

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