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Do Preclinical Testing Strategies Help Predict Human Hepatotoxic Potentials?

Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Rockville, Maryland, USA

Correspondence: Address correspondence to: Dr. Terry S. Peters, U.S. FDA, CDER, 9201 Corporate Blvd., Rockville, Maryland 20850, USA; e-mail:peterst{at}cder.fda.gov

Overt hepatotoxicity due to drug administration is a real and present issue in drug development and regulatory circles. Preclinical drug development is intended to identify potential risks and target tissues prior to introduction of new molecular entities into the human population. The standard regimen is testing at various multiples of the intended human therapeutic dose in at least 2 species of animals, one rodent (rats or mice), one non-rodent (dogs, nonhuman primates, minipigs, and rabbits, as examples) for at least two weeks of repeated dosing. Experience has shown that this regimen "works" most of the time. However, preclinical models are not infallible and are not always predictive. Whether the lack of predictivity is due to individual human genetic sensitivities, immunologically mediated phenomena, disease mediation or idiosyncratic reactions, the animal models are limited in detecting these characteristics and other low incidence phenomena. While it is uncommon for drug developers to continue development with products that elicit overt hepatic toxicity early in the animal testing, some products have made it through the approval process and then shown significant adverse effects. Some of the drugs (acetaminophen, isoniazid, trovafloxacin, troglitazone, bromfenac, clarithromycin, telithromycin) that have shown this propensity will be discussed in detail from early preclinical development to marketing and, in some instances, to limitations to usage or removal from the U.S. marketplace.

Key Words: Hepatotoxicity • drug development • preclinical testing

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