Telithromycin のイヌおよびサルを用いた反復経口投与毒性試験ならびにトキシコキネティックス

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In order to assess the oral toxicity of the test article telithromycin (TEL), we conducted a 30-day toxicity study and a 13-week toxicity study with a 12-week recovery period in Beagle dogs of both sexes and a 28-day toxicity study in Cynomolgus monkeys of both sexes. Toxicokinetic parameters were also evaluated in these studies. In 30 days study (0, 50, 150 and 300 mg/kg/day), the premature euthanasia was resulted in 1/3 females at 300mg/kg/day, which was considered to be related to compound-induced phospholipidosis-associated tubular nephropathy. Compound-related in-life observations consisted of vomiting (all doses), excessive salivation, a slight reduction in body weight gain and dehydration (at 150 and 300 mg/kg/day), and a loss of reflectivity of the tapetum lucidum (at 300mg/kg/day). Nephrotoxic findings (increased serum urea and/or creatinine and histopathological changes of tubular nephropathy) were observed at 150 and 300mg/kg/day and were considered, at least in part, attributable to the premature euthanasia. Compound-related phospholipidosis-like changes characterized by tissue infiltration with enlarged macrophages in the lungs, liver, gallbladder, mesenteric lymph nodes, intestinal tract, spleen, thymus and epididymides at 150 and 300mg/kg/day and in the stomach, lymph nodes, bone marrow, trachea and urethra at 300mg/kg. The no observed adverse effect dose level in this study is estimated to be 50 mg/kg/day. The pharmacokinetic studies showed high inter-animal variability and increase not in proportion with the dose. A marked increase in AUCs and Cmax was observed between Day 1 and Day 30 at 150 and 300mg/kg/day. The 13 weeks toxicity study followed by a 12-week recovery period (0, 20, 50 or 150 mg/kg/day) resulted in the death of 1/6 males at 150mg/kg/day which was considered related to compound-induced phospholipidosis associated with tubular nephropathy. As compound-related in-life observations, vomiting (all doses), excessive salivation (50 and 150mg/kg/day) and a slight reduction in body weight gain, changes of the tapetal fundus and slight increase in liver enzyme activities were noted at 150 mg/kg/day. Compoundrelated microscopic changes compatible with phospholipidosis were observed in the lungs at 50 and 150mg/kg/day and in the kidneys, liver, gallbladder, intestinal tract, lymph nodes, spleen, thymus and bone marrow at 150mg/kg/day. All the above-mentioned findings were totally reversible after a 12-week treatment-free period, with the exception of the pathological changes in tapetal fundus, lungs, mesenteric lymph nodes, kidneys, ureter and urinary bladder at 150 mg/kg/day which were only partially reversible. The no observable adverse effect level in this study was considered to be 50 mg/kg. The pharmacokinetic parameters in this study showed moderate inter-animal variability. Compared with dosage-increases, Cmax increase was lower and AUC increase was higher. AUC and Cmax between day 26 and day 89 were similar, whatever sex and dose. In the 28-day toxicity study in the Cynomolgus monkeys (0, 30, 60 and 120mg/kg/day), major drug-related findings at highest dose included emesis, soft feces, poor physical condition, body weight loss and reduced food consumption, and increases of liver enzyme activities and slightly increase of liver weights. The no observable adverse effect dose-level was considered to be 60mg/kg in this study. The pharmacokinetic parameters in this study showed moderate inter-animal variability. The increase of Cmax and AUCs were always higher than the ratio of the dose. Cmax and AUC between day 1 and day 28 increased at most by a factor of 1.8 and 2.0 respectively. Steady state of C24h was reached on day 8 in male or day 28 in female.
公益社団法人日本化学療法学会の論文
2003-09-30

Telithromycin のイヌおよびサルを用いた反復経口投与毒性試験ならびにトキシコキネティックス

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