Preclinical trials therapeutic index

The principle of estimating a therapeutic index prior to clinical trials typically involves determining the no observable adverse effect level (NOAEL) and comparing that to the projected human dose. In providing the estimate, the efficacious dose is typically obtained from in vitro data with human cells or tissues and in vivo preclinical pharmacology studies that involve animal disease models. Not infrequently the species used to estimate the toxic level is different from the species used to estimate an efficacious level. Thus the therapeutic index is not a true ratio as the units (species and/or conditions) are often different. On the other hand, if one were to obtain information relating to toxicity as well as efficacy from studies employing animal models of disease, a direct estimate of therapeutic index could be made provided that appropriate models had been characterized or validated in the relevant species. 

While the use of preclinical disease models offers many advantages, such as the potential for identification of biomarkers for clinical trials and a direct estimation of the therapeutic index, there are also disadvantages to this approach. The disadvantages can include a paucity of historical/baseline data and inherent variability of the model, the technical feasibility of using a particular disease model, the onset/severity of the injury in the animals as this may be different from humans, and the fact that the model may only emulate select aspects of the human pathophysiology of the disease [43], It is important to use behavioral models that have adequate sensitivity and specificity to allow for correlation with morphological and biochemical findings, as in the area of spinal cord injury. 

Finally, ASKA mice should provide crucial information regarding the therapeutic index. ASKA-based in-vivo studies will be able to establish mechanism and target-based efficacy and toxicity for most protein kinases. Such information should prove useful in the preclinical testing of development candidates, because it will allow distinction between mechanism (target)-based and compound (off-target)-based toxicities [35], At this point, we would like to challenge the scientific community and express our interest in the development of p38-ASKA mice, to either promote or discourage the numerous clinical trials of p38 for various indications and to clarify the associated liver toxicity upon treatment of patients with p38 inhibitors. 

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