Toxicity testing, repeat-dose interpretation

Currently, there are no validated and regulatory accepted in vitro methods for assessing repeated dose toxicity. Numerous in vitro systems have been developed over the last decades and have been discussed and summarized in recent ECVAM reports on repeated dose toxicity testing (Worth and Balls 2002, Prieto et al. 2005, Prieto et al. 2006). Human in vitro data, particularly on kinetics and metabolism, and in vitro test data from well-characterized target organ and target system models on, e.g., mode of action(s)/mechanism(s) of toxicity may be useful in the interpretation of observed repeated dose toxicity. 

While useful for evaluating substrate reduction and tissue distribution, the knockout mouse also presented specific challenges to the preclinical development program. After repeated administration of rhGAA, a predictable hypersensitivity response to the recombinant human protein was observed. Frequently this reaction resulted in morbidity and mortality associated with test article administration. This hypersensitivity reaction responded to diphenhydramine prior to, and as necessary, during dosing however, such intervention complicated interpretation of toxicity studies. 

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