Nimesulide

Nimesulide is a non-steroidal anti-inflammatory drug with analgesic and antipyretic properties which acts as an inhibitor of prostaglandin synthesis enzyme cyclo-oxygenase.

Cyclo-oxygenase produces prostaglandins, some of them being implicated in the development and maintenance of inflammation.

Nimesulide is well absorbed when given by mouth. After a single dose of 100mg nimesulide a peak plasma level of 3-4 mg/l is reached in adults after 2-3 hours. AUC=20-35 mg h/l. No statistically significant difference has been found between these figures and those seen after 100mg given twice daily for 7 days.

Up to 97.5% binds to plasma proteins.

Nimesulide is extensively metabolised in the liver following multiple pathways, including cytochrome P450 (CYP) 2C9 isoenzymes. Therefore, there is the potential for a drug interaction with concomitant administration of drugs which are metabolised by CYP2C9. The main metabolite is the para-hydroxy derivative which is also pharmacologically active. The lag time before the appearance of this metabolite in the circulation is short (about 0.8 hour) but its formation constant is not high and is considerably lower than the absorption constant of nimesulide. Hydroxynimesulide is the only metabolite found in plasma and it is almost completely conjugated. T_1⁄2 is between 3.2 and 6 hours.

Nimesulide is excreted mainly in the urine (approximately 50% of the administered dose). Only 1-3% is excreted as the unmodified compound. Hydroxynimesulide, the main metabolite is found only as a glucuronate. Approximately 29% of the dose is excreted after metabolism in the faeces.

The kinetic profile of nimesulide was unchanged in the elderly after acute and repeated doses.

In an acute experimental study carried out in patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min) versus healthy volunteers, peak plasma levels of nimesulide and its main metabolite were not higher than in healthy volunteers. AUC and t_1/2 beta were 50% higher, but where always within the range of kinetic values observed with nimesulide in healthy volunteers. Repeated administration did not cause accumulation. Nimesulide is contra-indicated in patients with hepatic impairment.

When nimesulide 3% w/w gel is applied topically, plasma concentrations of nimesulide are very low in comparison with those achieved following oral intake. After a single application of 200mg of nimesulide, in the gel form, the highest plasma level of 9.77 ng/ml was noted after 24 hours. No trace of the main metabolite 4-hydroxy-nimesulide, was detected. At steady-state (day 8) peak plasma concentrations were higher (37.25 ± 13.25 ng/ml) but almost 100 times lower than those measured following repeated oral administration.

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In repeated dose toxicity studies, nimesulide showed gastrointestinal, renal and hepatic toxicity. In reproductive toxicity studies, embryotoxic and teratogenic effects (skeletal malformations, dilatation of cerebral ventricles) were observed in rabbits, but not in rats, at maternally non-toxic dose levels. In rats, increased mortality of offspring was observed in the early postnatal period and nimesulide showed adverse effects on fertility.

The local tolerance and the irritation and sensitisation potential of nimesulide 3% w/w gel have been tested in several recognised animal models. The results of these studies indicate that nimesulide 3% w/w gel is well tolerated.