Safety pharmacology animal models

Safety Pharmacology. It is important to investigate the potential for unwanted pharmacological activity in appropriate animal models and to incorporate monitoring for these activities in the toxicity studies. 

Hamlin, R.L., Non-drug-related electrocardiographic features in animal models in safety pharmacology, /. Pharmacol. Toxicol. Methods, 52, 60-76, 2005. 

In addition to toxicity and safety data, the preclini-cal package to start clinical studies also contains information on the pharmacology, the pharmacokinetics and metabolism and the galenical aspects of the compound. As a rule there is evidence of pharmacological activity and, if possible, of therapeutic activity in one or more animal models of disease. Ideally there is also information on the in vivo concentration effect relationship. 

The commencement of human pharmacology clinical trials (T ilH trials) can lead to a range of emotions for clinical researchers. It is a time of excitement (and quite possibly relief) that the drug has reached this milestone and a time of anticipation and hopeful expectation. Additionally, and possibly more so, it is a time of trepidation and anxiousness. As noted in Section 4.5, no animal model is a perfect predictor of the precise effects of the drug in humans, and there is the ever present possibility that serious safety issues may arise. On relatively rare occasions, life-threatening, drug-induced conditions have occurred in subjects in human pharmacology clinical trials. 

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. 

The use of nonrelevant animal species is discouraged as the results of such studies may be misleading (per ICH S6). Therefore the next option, when available, is to substitute a relevant transgenic animal model for a pharmacologically relevant species. Transgenic animal models for human EpCAM have been developed, but they either have a different tissue expression pattern from that seen in humans [41,43] or the model has not been validated [40], making them unsuitable for the evaluation of the safety of anti-EpCAM immunotherapeutics. 

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