Therapeutic ReviewsPreclinical Development of New Drugs that Enhance Thyroid Hormone Metabolism and Clearance: Inadequacy of Using Rats as an Animal Model for Predicting Human Risks in an IND and NDAWu, Kuei-Meng*; Farrelly, James G.Author Information Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852 *Address for correspondence: HFD-530, CDER, FDA, 5600 Fisher's Lane, Rockville, MD 20852. E-mail: [email protected] This article is not an official FDA guidance or policy statement. No official endorsement by the FDA is intended. CDER/FDA has taken into account the unique sensitivity of rats to thyroid tumors by the mechanisms discussed in this article, and sometimes has discounted thyroid tumor findings resulting from the said mechanisms as relevant to humans. American Journal of Therapeutics: March 2006 - Volume 13 - Issue 2 - p 141-144 doi: 10.1097/01.mjt.0000209673.01885.b0 Buy Metrics Abstract New drugs that enhance metabolism or clearance of thyroid hormones in rats often trigger a sequence of toxicity events during chronic administration: reduction of thyroxine, elevation of thyroid-stimulating hormone (TSH) levels, and thyroid gland hyperfunction/growth. Hepatocellular hypertrophy and thyroid follicular hyperplasia are often observed with increased liver and thyroid organ weights. This unique toxicity profile seems to be species-specific because the thyroxine in rodents is metabolized rapidly, without thyroid hormone-binding globulin that serves as a reserve, as in humans. Thus, elevations of TSH were not reported in humans for drugs such as delavirdine, fluvastatin, nicardipine, phenobarbital, simvastatin, and spironolactone, all of which produce thyroid hyperplasia or tumors in rats. Further, the human thyroid is less sensitive to prolonged TSH stimulation than that of the rat (eg, endemic goiter patients with high TSH due to iodine deficiency do not develop thyroid cancer). In view of the species difference in sensitivity of the thyroid between rodents and humans, using the rat as an animal model to explore target organs of toxicity for a new drug that significantly enhances thyroid hormone metabolism/clearance and increases TSH levels would not be adequate. In this case, a compromised and dysfunctional hypothalamo-pituitary-thyroid system would confound the toxicity profile explored in preclinical toxicity testing and render the model an inadequate risk predictor for the new drug in humans. Under such conditions, IND and NDA sponsors of drugs exhibiting this activity profile should be encouraged to use alternative animal species for toxicity exploration to provide a more meaningful human risk prediction. © 2006 Lippincott Williams & Wilkins, Inc.