Animal Models their Predictive Value

Studies in pre-clinical models with human tumours are often carried out in (immuno)defi-cient mice. However, particularly in the case of monoclonal antibody-directed therapy, it is important to recognize that these models, while useful, frequently over-predict activity and under-predict toxicity because the target antigen is tumour-specific in the animal but only tumour-associated in man. 

Other limitations of mouse/rat models are that tumour growth is different in the animal model compared to the situation in man.Tumour growth is more rapid in the rat/mouse model which has an effect on vascularization and intra-tumoural pressure for example. These factors can, as discussed in Section 8.4, have great impact on tumour penetration and uptake of the MAb-based drug-targeting constructs. 

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The use of microorganisms as a complementary tool in the study of drug metabolism is certainly becoming more popular. The examples cited above provide additional evidence of the utility of such systems as alternative in vitro models for investigating drug metabolism in humans. However, as mentioned above, no in vitro model could ever completely replace animal experimentation in medical research, and the predictive value of microbial systems, even if they frequently correlate with their animal counterpart, is questionable. Nevertheless, microorganisms can be used as a reliable and efficient alternative to small animals or... 

Biopharmaceuticals represent a broad but discrete class of large molecular weight therapeutic entities that are characterized by their specific pharmacological activities and distinctive pharmacokinetics. The selection of an appropriate animal model is dependent on a combination of PD and PK factors. As described in this chapter, it is essential to understand the relationship of the basic pharmacology of a biopharmaceutical (signaling, receptor presence, binding properties, etc.) and the associated PK properties to that expected in humans, in order to select animal species that will have the most predictive value in safety assessments. 

Model Parameters. Concentration factors were determined for large numbers of bivalve molluscs. Values were obtained by determining the concentration of stable and/or radioactive nuclides in animals and water that were collected directly from the environment and that were sampled in laboratory experiments. These data were compiled for use in models to predict radionuclide concentrations in whole organisms or their tissues. In general, for bivalve molluscs a single value is given for each element. 

In order to assess the risk from topical exposure a number of investigators have sought animal models that could predict percutaneous absorption rates of chemicals in humans. Considerable efforts by Wester and Maibach (2-6) have shown that monkeys and pigs give dermal absorption data most comparable to humans with a range of drugs and pesticides which varied in their physicochemical properties as well as use. A similar rank order for species comparisons has been observed in in vitro (12-14) absorption data which in most cases exceeded the human values (Table I). For this reason, and because of the availability of rhesus monkeys within our facility, dermal absorption studies with rhesus monkeys were considered an appropriate model. 

Barratt and co-workers used neural net-based QSAR/QSTR methods to relate the severity of skin corrosivity of acids to parameters that model their skin permeability and cytotoxicity (90,91). The classification predictions were in agreement with those in the training set for 26 of the 27 acids. The methods provided useful procedures for the prediction of the skin corrosivity potentials of severely corrosive acids, which avoid the use of experimental animals and demonstrate the value of in vitro cytotoxicity parameters as inputs for QSAR analysis. 

There are, however, at least four aspects of 5 0 variation in the biosphere which can affect this correlation and, as such, could account for the variation in the data. The two predictive models differ in the emphasis placed on each of these aspects. First, animal 8 0 values are not expected to vaiy predictably with rainfall and surface water in cases where animals obtain the majority of their body water from plants and where plant values vary independently of surface water values. For example, within Australia there is little continental variation in rainfall 5 0 values and little surface water for... 

Rougier et al. [ROU 07] have developed a predictive model of the a of food media rich in animal protein (such as fish, pork and beef meats), salted or high in fats. Their works have been carried out with gelatin to which salt and/or fats were added. They have measured the sorption curves using the Baucour and Daudin method [BAU 00]. The obtained values of a have then been adjusted with the Ferro Fontan model [FER 82] ... 

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