Pharmacokinetic and Toxicokinetic Studies of Potential Antifungal Compounds, KAF-200522 and KAF-200522·HCl, in Animal Models

Recent researches on clinically used triazole antifungal reagents are focused on their pharmacokinetic disadvantage which increases the probability of inducing adverse effects in patients. For this point, in the present laboratory, Chemon Inc., has investigated new antifungal reactive compounds, KAF-200522 and its chloride form, KAF-200522 · HCl, which has a modified triazole structure. Pharmacokinetic data were measured with LC-MS/MS in male mice which were orally treated with the above compounds at 10 ㎎/㎏. T max and t ½ of KAF-200522 · HCl were comparable to KAF-200522, but AUC and C max were 1.4 and 1.6 times higher than those of KAF-200522, respectively. In beagle dogs, AUC and C max of KAF-200522 · HCl were 2.7 and 1.4 times higher than those of KAF-200522, and t ½ was 3.5 times higher than that of KAF-200522. Moreover, in beagle dogs, the oral bioavailability value of KAF-200522 · HCl was revealed as 31.0% to contrast to 6.2% of KAF-200522. In 1-week repeated oral treatment toxicity study of KAF-200522 in male rats, inhibition of body weight gain was observed in 120 ㎎/㎏ treatment group, and loss of body weight was observed in 600 ㎎/㎏ treatment group. In the toxicokinetic study of KAF-200522, no accumulation after the systemic exposure was observed. In conclusion, as to the new antifungal drug development, KAF-200522 · HCl was considered to be advantageous in pharmacokinetic characteristics compared to KAF-200522.