SUBACUTE AND CHRONIC ORAL TOXICITY OF LORNOXICAM IN CYNOMOLGUS MONKEYS

Lornoxicam is a novel non-steroidal anti-inflammatory compound in the same chemical class as piroxicam and tenoxicam, with potent anti-infla mmatory, antipyretic and analgesic activity. As part of the preclinica l safety programme, its toxicity was evaluated in a dose-range-finding and 52-wk toxicity study in cynomolgus monkeys. In the dose-range-fin ding study, five groups of monkeys (two per sex per group) were dosed orally by gavage for 6 wk with 0, 0.25, 0.5, 1.0 or 2.0 mg lornoxicam/ kg/day. Drug-related toxicity was observed in the 1.0 and 2.0 mg/kg/da y dose groups only. This included mortality, diarrhoea, prostration, d ecreased body weight gain and food consumption, faecal occult blood, a naemia, leucocytosis, hypoalbuminaemia, gastrointestinal erosions and ulcerations. On the basis of these results, four groups of monkeys (si x per sex per group) were given the compound orally by nasogastric int ubation at dose levels of 0, 0.125, 0.25 or 0.5 mg/kg/day for 52 wk. T he high-dose level was increased to 0.6 mg/kg/day from wk 39 to wk 52. Treatment was followed by a 4-wk recovery period for two animals per sex per group. Histologically, drug-related changes seen were gastroin testinal erosions, ulcerations and inflammation in males and females a t 0.5/0.6 mg/kg/day. Treatment-related clinicopathological findings in cluded decreased haematocrit and hypoproteinaemia (group 0.5/0.6 mg/kg /day males), and hypoalbuminaemia (group 0.5/0.6 mg/kg/day males and f emales). None of these changes were present after the recovery period, thus indicating reversibility. Plasma concentration of lornoxicam mea sured 2 hr after dosing increased in a dose proportional manner. The e stimated area under the curve (AUG) at steady state increased in a dos e-proportional manner and at 0.25 mg/kg was three- to fivefold higher than the human AUC following a 16 mg dose (8 mg b.i.d.). The no-observ ed-effect level in the chronic toxicity study was 0.25 mg/kg/day. (C) 1997 Elsevier Science Ltd.