Toxicological Profile and Safety Evaluation of Antifungal Azole Derivatives

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Abstract
Summary: For the development of new sys‐temically acting, oral antifungal azoles, it is of key importance to compare them with ketoconazole, the first available drug in this therapeutic class. Ketoconazole is a major breakthrough although hepatic side‐effects as well as interactions with mammalian steroids might rarely occur during prolonged treatment. The prediction of these side‐effects is difficult but the potential to interact with mammalian cytochrome P‐450 enzymes is considered to be important. Therefore, for the selection of itraconazole a multidiscipli‐nary approach was applied to study this potential. The present paper deals with the toxicological profile of itraconazole and its safety evaluation. In addition, a further comparison with ketoconazole and also with fluconazole is provided, in so far sufficient information is available. For the liver as a potential target organ, the available data indicate that itraconazole is not a predictable hepatotoxic drug in man. The major endocrine targets for overdosing with antifungal azoles are the adrenal cortex and the gonads. Endocrine studies show that itraconazole is not bearing a potential to interfere with steroid hormones in patients, which is a major improvement when compared to ketoconazole. In rats, elevation of serum cholesterol is observed especially after chronic exposure to itraconazole. This species‐specific phenomenon leads at toxic dose levels to secondary events, especially in the long‐term toxicity studies. In man, including those with existing hypercholesterolemia, serum cholesterol is not adversely affected by itraconazole. In pregnant rats, ketoconazole was shown to be teratogenic at high, toxic doses. The same observation has been made for itraconazole and this also might be true for fluconazole. On the other hand, all three azoles are not teratogenic in the rabbit species. Studies with itraconazole in adre‐nalectomized rats and in rats given exogenous arachidonic acid indicate that adrenal effects occurring at toxic dose levels are important mediators for teratogenicity. Since itraconazole does not affect adrenal function in patients, the teratogenic risk is estimated to be low.b