Physiologically based models

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent chemical or metabolite in an animal system. There are two types of pharmacokinetic models data-based and physiologically-based. A data-based model divides the animal system into a series of compartments which, in general, do not represent real, identifiable anatomic regions of the body whereby the physiologically-based model compartments represent real anatomic regions of the body. 

Physiologically Based Pharmacodynamic (PBPD) Model—A type of physiologically-based dose-response model which quantitatively describes the relationship between target tissue dose and toxic end points. These models advance the importance of physiologically based models in that they clearly describe the biological effect (response) produced by the system following exposure to an exogenous substance. 

Blakey GE, Nestorov lA, Arundel PA, Aarons LJ, Rowland M. Quantitative structure-pharmacokinetics relationships I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat. J Pharmacokinet Biopharm 1997 Jun 25(3) 277-312. Erratum in J Pharmacokinet Biopharm 1998 Feb 26(l) 131. 

Parrott, N Paquereau, N Coassolo, P Lave, Th. An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery. f Pharm. Sci. 2005, 94, 2327-2343. 

O Flaherty EJ. 1991a. Physiologically based models for bone-seeking elements. II. Kinetics of lead disposition in rats. Toxicol Appl Pharmacol 111 313-331. 

The physiologically based model developed by Willman et al. [53, 54], for the prediction of both rat and human Fibs, was shown to be predictive for the human situation if passively transported compounds were studied. In their study, they used a semiempirical formula for the prediction of human permeability trained with a set of 119 passively transported drugs that did not show solubility or dissolution rate-limited absorption. 

Compartmental Models Versus Physiologically-based Models... 

Although compartmental models and physiologically-based models may at first, seem quite different, and are usually treated as two different classes of models, both approaches are actually similar [17]. When appropriately defined, probably any PB-PK model can be written as a compartmental model and vice versa. This can be seen by comparing the models in Figures 13.1 and 13.3, and their mathematical descriptions in Eq. 13.1 and 13.5. 

Sakaeda et cd. [59] described an example of physiologically-based modelling for a lung-specific pro-drug of the antibiotic drug ceftazidime. 

Haddad, S., G. Charest-Tardif, and K. Krishnan. 2000b. Physiologically based modelling of the maximal effect of metabolic interactions on the kinetics of components of complex chemical mixtures. J. Toxicol. Environ. Health 61 PartA 209-223. 

Another important advance adding to the value of PBPK modeling in the pharmaceutical industry are physiological, mechanistic models developed to describe oral absorption in humans and preclinical species. Oral absorption is a complex process determined by the interplay of physiological and biochemical processes, physicochemical properties of the compound and formulation factors. Physiologically based models to predict oral absorption in animals and humans have recently been reviewed [18, 19] and several models are now commercially available. The commercial models have not been published in detail because of proprietary reasons but in essence they are transit models segmenting the gastrointestinal tract... 

Physiologically based models show improved performance over more empirical methods. The PBPK approach is based upon solid physiological principles and can be extended to include additional relevant processes. Also, besides satisfactory... 

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