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-inflammatory, antipyretic and analgesic activity. As part of the preclinical safety programme, its toxicity was evaluated in a dose-range-finding and 52-wk toxicity study in cynomolgus monkeys. In the dose-range-finding 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/day dose groups only. This included mortality, diarrhoea, prostration, decreased body weight gain and food consumption, faecal occult blood, anaemia, leucocytosis, hypoalbuminaemia, gastrointestinal erosions and ulcerations. On the basis of these results, four groups of monkeys (six per sex per group) were given the compound orally by nasogastric intubation at dose levels of 0, 0.125, 0.25 or 0.5 mg/kg/day for 52 wk. The 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 gastrointestinal erosions, ulcerations and inflammation in males and females at 0.5/0.6 mg/kg/day. Treatment-related clinicopathological findings included 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 females). None of these changes were present after the recovery period, thus indicating reversibility. Plasma concentration of lornoxicam measured 2 hr after dosing increased in a dose proportional manner. The estimated area under the curve (AUC) at steady state increased in a dose-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-observed-effect level in the chronic toxicity study was 0.25 mg/kg/day.