Physiologically based models model formulation

A recent shift in emphasis has been from simple DMPK parameters to a more physiological interrogation of the data. Such physiological based pharmacokinetic modelling may provide mechanistic links to understand the influence of drug delivery formulations, or even the relationship between efficacy and toxicity at the tissue level. However literature examples of the benefit of such detailed analysis are sparse, or even lacking. 

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... 

Once the structure of the PBPK model is formulated, the next step is specifying the model parameters. These can be classified into a chemical-independent set of parameters (such as physiological characteristics, tissue volumes, and blood flow rates) and a chemical-specific set (such as blood/tissue partition coefficients, and metabolic biotransformation parameters). Values for the chemical-independent parameters are usually obtained from the scientific literature and databases of physiological parameters. Specification of chemical-specific parameter values is generally more challenging. Values for one or more chemical-specific parameters may also be available in the literature and databases of biochemical and metabolic data. Values for parameters that are not expected to have substantial interspecies differences (e.g., tissue/blood partition coefficients) can be imputed based on parameter values in animals. Parameter values can also be estimated by conducting in vitro experiments with human tissue. Partitioning of a chemical between tissues can be obtained by vial equilibration or equilibrium dialysis studies, and metabolic parameters can be estimated from in vitro metabolic systems such as microsomal and isolated hepatocyte syterns. Parameters not available from the aforementioned sources can be estimated directly from in vivo data, as discussed in Section 43.4.5. 

DBS appears to work by freeing thalamocortical and brainstem motor systems from abnormal and disruptive basal ganglia influences ([67], p. 202). At a local scale DBS appears to inhibit the soma of nerve cells and to activate the axons [42]. At an intermediate scale, DBS appears to alter the dynamics in the GPi-STN network [10]. At a distant scale, DBS appears to normalize the activity in the supplementary motor area and in the premotor cortex [67]. While many hypotheses have been formulated, the experimental results are difficult to reconcile especially when several physiological scales are considered. We now present a computational model based on a population density approach. 

More sophisticated approaches to predict the extent of oral absorption of drugs use mathematical models based on the known physiology and utilizing simple physicochemical measurements as input. The GastroPlus [4] program is a commercial tool that utilizes an advanced compartmental and transit model, based on the work of Amidon and Yu [5], and allows what-if questions to be posed to enable pharmaceutical optimization (see Chapter 17). For instance, the impact of morphology, formulation, and/or particle size changes, and sensitivity analysis to include errors in parameters on the prediction, can be considered. 

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