MIMS Classification(s): Non-steroidal Anti-inflammatory Agent (NSAID).
Pharmacology: Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. Etoricoxib is a potent, orally active, highly selective cyclooxygenase-2 (COX-2) inhibitor within and above the clinical dose range. Two isoforms of cyclo-oxygenase have been
identified: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). COX-1 is responsible for prostaglandin-mediated normal physiologic functions such as gastric cytoprotection and platelet aggregation. Inhibition of COX-1 by nonselective NSAIDs has been associated with gastric damage and platelet inhibition. COX-2 has been shown to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. Selective inhibition of COX-2 by Etoricoxib decreases these clinical signs and symptoms with decreased GI toxicity and without effects on platelet function.
Etoricoxib produces dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily.
Platelet Function: Multiple doses of Etoricoxib up to 150 mg administered daily up to nine days have no effect on bleeding time. There is no inhibition of ex vivo arachidonic acid- or collagen-induced platelet aggregation at steady state with doses of Etoricoxib up to 150 mg. These findings are consistent with the COX-2 selectivity of Etoricoxib.
Pharmacokinetics: Absorption: Orally administered Etoricoxib is well absorbed. The absolute bioavailability is approximately 100%. The pharmacokinetics of Etoricoxib are linear across the clinical dose range.
A standard meal had no clinically meaningful effect on the extent or rate of absorption of a dose of Etoricoxib 120 mg. Etoricoxib can be administered without regard to food.
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 μg/mL. The volume of distribution at steady state (Vdss) was approximately 120 L in humans.
Etoricoxib crosses the placenta in rats and rabbits and the blood barrier in rats.
Biotransformation: Etoricoxib is extensively metabolized with <1% of a dose received in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes.
Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of Etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.
Elimination: Elimination of Etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations of Etoricoxib are reached within seven days of once daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours.
The plasma clearance after a 25-mg intravenous dose is estimated to be approximately 50 mL/min.
Characteristics in patients: Elderly patients: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young.
Gender: The pharmacokinetics of Etoricoxib are similar between men and women.
Hepatic impairment: Patients with mild hepatic dysfunction (Child-Pugh score 5-6) administered Etoricoxib 60 mg once daily had an approximately 16% higher mean AUC as compared to healthy subjects given the same regimen. Patients with moderate hepatic dysfunction (Child-Pugh score 7-9) administered Etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects given Etoricoxib 60 mg once daily. Etoricoxib 30 mg once daily has not been studied in this population. There are no clinical or pharmacokinetic data in patients with severe hepatic dysfunction (Child-Pugh score ≥ 10).
Renal impairment: The pharmacokinetics of a single dose of Etoricoxib 120 mg in patients with moderate to severe renal insufficiency and patients with end-stage renal disease on hemodialysis were not significantly different from those in healthy subjects. Hemodialysis contributed negligibly to elimination (dialysis clearance approximately 50 mL/min).
Pediatric patients: The pharmacokinetics of Etoricoxib in pediatric patients (< 12 years old) have not been studied.
Pharmacokinetics in adolescents (aged 12 to 17) weighing 40 to 60 kg given Etoricoxib 60 mg once daily and adolescents > 60 Kg given Etoricoxib 90 mg once daily were similar to the pharmacokinetics in adults given Etoricoxib 90 mg once daily. Safety and effectiveness of Etoricoxib in pediatric patients have not been established.