Preclinical Pharmacodynamic and Pharmacokinetic Studies of Investigational New Drugs

摘要

Individual studies have been conducted to determine the identity of the urinary metabolites of artelinic acid eliminated by dogs and to investigate the dose-related pharmacodynamic effects of artelinic acid, as assessed by signs of clinical and pathological toxicity, in male and female rats and dogs. Using LC/MS/MS methodology, glucuronides of artelinic acid, hydroxy artelinic acid, DQHS, and hydroxy DQHS were tentatively identified in urine collected from dogs dosed with artelinic acid. In rats given 14 consecutive daily oral doses of artelinic acid of 0, 10, 20, 40, SO, or 320 mg/kg/day or IM doses of 12.5 mg/kg/ day of arteether, body weight loss and mortality were observed at an artelinic acid dose of 320 mg/kg/day. Biologically relevant changes in hematology parameters observed on Day 21 included: increases in mean reticulocyte counts at artelinic acid doses of 20, 40, 80, and 320 mg/kg/day; and mild increases in erythrocyte MCV values at artelinic acid doses of 20 and 80 mg/kg/day. A biologically relevant decrease in mean ALP activity was also observed in rats in the 320 mg/kg/day dose group. At artelinic acid doses of 40 and 80 mg/kg/day and an arteether dose of 12.5 mg/kg/day, neuropathological lesions observed in the hind brain consisted of neuronal degeneration of the trapezoid nucleus; at an artelinic acid dose of 320 mg/kg/day, the lesions also included multiple nuclei in the hind brain. In dogs given 14 consecutive daily oral doses of artelinic acid of 0, 20, 40, 80, or 320 mg/kg/day or IM doses of 20 mg/kg/day of arteether, body weight loss was noted for dogs in the 320 mg/kg/day artelinic acid and the arteether dose groups. Potentially drug-related decreases in RBC, hemoglobin, hematocrit, and/or reticulocyte counts were observed in the 20, 40, 80, and 320 mg/kg/day artelinic acid and the arteether dose groups.