Strategies for handling unexpected endocrine findings in early safety assessment.
Early assessment of the endocrine toxicity of pharmaceuticals has received increasing scientific attention due to the important issue of endocrine disrupters, and the need to evaluate mechanisms and relevance to humans of early toxicity findings in animals. Pharmaceuticals can directly alter an endocrine organ, or indirectly regulatory systems. The strategy for handling unexpected endocrine findings in early toxicity studies is by definition extremely variable and should be adapted case by case. Using three examples: (i) thyroid hyperplasia; (ii) prolactin-induced mammary gland hyperplasia in rats; and (iii) aromatase inhibition, the usefulness and limitation of serum endocrine analyses in classical toxicological studies, the need for specific mechanistic studies and the major importance of integration between pharmacodynamic, pharmacokinetic and toxicological data will be discussed. Finally, the importance of assessment of relevance and the extrapolation of preclinical findings to humans at an early stage in clinical development is highlighted.
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Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. rdcoster@janbe.jnj.com
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