In vivo preclinical model trial

In vivo preclinical model trial against a collagen matrix... 

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. 

DHA-paclitaxel (Taxoprexin ) 62 (Luitpold) is being evaluated in a Phase III trial for the treatment of advanced non-small cell lung cancer in combination with carboplatin,136 as well against a variety of cancers in Phase II trials. DHA-paclitaxel 62,137 139 which is the C-2 docosahexaenoic acid (DHA) ester of paclitaxel 60, was licensed by Luitpold from Protarga in 2003. Polyunsaturated fatty acids have been reported to be taken up by tumour cells at a higher rate than normal cells and, as a consequence, a polyunsaturated fatty ester such as DHA-paclitaxel 62 may be absorbed more specifically in tumour cells. In preclinical studies, DHA-paclitaxel 62 exhibited increased activity in mice xenograft models and was more stable in vivo than paclitaxel 60. However, DHA-paclitaxel 62 may still suffer from efflux problems associated with paclitaxel 60 and docetaxel resistant tumours. 

Several preclinical studies, originally designed to support the above clinical trials, have been carried out. From these it was determined that m-THPC is not metabolized in vivo and virtually all the drag is eliminated via the liver. Pharmacokinetic data derived from animal studies with m-THPC led to the prediction that this substance would show rapid clearance from plasma in humans. Surprisingly, however, this was only observed in the animal models (dog, rabbit, rat), not in the human populations. This dichotomy stands as a cogent reminder that caution must always be exercised in translating animal-model data into human-dosing decisions [225]. 

Johnson JI, Decker S, Zaharevitz D, Rubinstein LV, Venditti JM, Schepartz S, Kalyandmg S, Christian M, Arbuck S, Hollingshead M, Sausville EA. Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials. Br J Cancer 2001 84 1424-31. 

Figure 19.1 Schematic view of the toxicity profiling process in drug discovery and stages of preclinical evaluation prior to going into first human trials (note that the results of in vitro and in vivo toxicity assays are used to refine in silico models).

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