Axcel Etoricoxib Mechanism of Action

Pharmacology: Mechanism of Action: Etoricoxib is a nonsteroidal 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 cyclooxygenase 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.
Pharmacokinetics: Absorption: In studies specifically designated to measure the onset of action of etoricoxib, the onset of action occurred as early as 24 minutes after dosing. Orally administered etoricoxib is well absorbed. The mean oral bioavailability is approximately 100%. Following 120 mg once-daily dosing to steady state, the peak plasma concentration (geometric mean C_max = 3.6 mcg/mL) was observed at approximately 1 hour (T_max) after administration to fasted adults. The geometric mean AUC_0-24hr was 37.8 mcg*hr/mL. The pharmacokinetics of etoricoxib are linear across the clinical dose range. A standard meal had no effect on the extent or rate of absorption of etoricoxib after administration of a 120 mg dose. In clinical trials, etoricoxib was administered without regard to food.
Distribution: Etoricoxib is approximately 92% bound to plasma protein over the range of concentration of 0.05 to 5 mcg/mL. The volume of distribution of steady state (V_dss) is approximately 120L in humans.
Metabolism: Etoricoxib is extensively metabolized with <1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by cytochrome P450 (CYP) enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. Five metabolites have been identified in man. The principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.
Elimination: Following administration of a single 25 mg radiolabeled intravenous dose of etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in feces, mostly as metabolites. Less than 2% was recovered as unchanged drug. 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.