title: Comparative toxicological assessment of a water-soluble azole administered both orally and by intravenous continuous infusion in cynomolgus monkeys.
abstract: The water-soluble azole, 4-[1-[(3-methylaminoacetoxymethyl-pyridin-2-yl)-methyl-carbamoyloxy]- ethyl]-1-[(2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2- (2,5-difluoro-phenyl)-2-hydroxy-butyl]-1H-[1,2,4]triazol-4-ium chloride hydrochloride (hereinafter referred to as WSA), is a new water-soluble triazole anti-fungal compound. WSA is rapidly converted into its active metabolite after administration by either the intravenous or oral route. The clinical effects of WSA are expected to be consistent whether it is administered by injection (intravenous) or orally. To evaluate and compare the toxicities of WSA via oral and intravenous administration, repeated toxicity studies of WSA were conducted in cynomolgus monkeys (oral dosage levels: 0, 10, 30 and 90 mg/kg/day over a 4-week period; intravenous infusion dosage levels: 0, 10, 30 and 60 mg/kg/day over a 2-week period). In addition, a 2-week oral toxicity study of the active metabolite of WSA was conducted with similar dosages (0, 10, 30 and 90 mg/kg/day). From the results obtained from the evaluation, hepatotoxicity (liver) and endocrinological toxicity (adrenals) were the major toxicities, a finding which is comparable to other previously tested azole compounds. In the 4-week oral toxicity study, the lethal dose of WSA was determined to be 90 mg/kg. However, no animal mortality was observed during the 2-week intravenous continuous infusion study. The toxicokinetics (TK) profile of WSA at 10 and 30 mg/kg dosages illustrated a rapid, dose-dependent conversion of WSA to its active metabolite, and the plasma levels of Cmax and AUC were well correlated to their toxicities. However, at high dosages (60 and 90 mg/kg), WSA demonstrated high exposure beyond the dose-proportional manner. Overall, the results obtained indicate that maintaining an effective concentration and a non-toxic dosage level would be manageable by utilizing an initial intravenous continuous infusion followed by oral administration.
authors.affiliation: Department of Preclinical Science, Nippon Roche Research Center, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Horii
mesh_terms: D000284:Administration, Oral; D000311:Adrenal Glands / Q000187:drug effects / Q000473:pathology; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D019540:Area Under Curve; D001393:Azoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D012995:Solubility; D018675:Toxicity Tests; D014867:Water
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D014867:Water