Repeat-dose toxicity studies biopharmaceuticals

Repeat-Dose Toxicity Studies Typically toxicity studies are performed in two animal species. However, for toxicity studies for which there is only one relevant animal species, these studies may be performed using one animal species. When two animal species show the same toxicity profile in short-term studies, only one animal species may be used in long-term studies. Comparison of toxicity profiles means comparing the type and severity of any toxicity observed. However, biopharmaceuticals with a low toxicity may display no toxicity at high doses in some cases. It such cases it may still be important to select one species for assessment of chronic toxicity. More important, in cases where toxicity has not been clearly demonstrated justification of human... 

Immunotoxicity testing guidelines exist for small molecules where the toxicology is largely unpredictable and rodent species are typically used [4]. Despite the lack of a specific guidance on immunotoxicity evaluation until now, most biopharmaceuticals have assessed the immunotoxic potential of the biophar-maceutical as a part of general single- and/or repeat-dose toxicity studies [5,23]. 

Four-week toxicology studies in rodent and nonrodent The four-week studies are designed for subchronic exposure of rodents and nonrodents to the test article. These studies also look at reversibility of any toxicity observed. Many times these are the pivotal studies used to support the first in human dosing. Toxicokinetic assessments are generally included in repeat-dose toxicity studies. When testing biopharmaceuticals, studies also include assessment and characterization of immune response (immunogenicity). 

The usual GLP 30- or 60-day repeat-dose toxicology study with a recovery group offers an opportunity to perform a more systematic investigation of the more subtle pharmacodynamic or toxicologic effects of biopharmaceuticals than those endpoints usually incorporated into such protocols. Some of these demand tissue samples, but many involve noninvasive biomarkers that can be carried forward into early phase human studies. These might include CNS assessments, inflammation and immune activation or suppression, cell proliferation or apoptosis in tissue samples, and end-organ toxicities. 

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