Sign Out
Therapeutic Class: ARCOXIA (etoricoxib) is a member of a class of arthritis/analgesia medications called Coxibs. ARCOXIA is a highly selective inhibitor of cyclooxygenase-2 (COX-2).
Pharmacology: Mechanism of Action: ARCOXIA is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. ARCOXIA 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.
Across clinical pharmacology studies, ARCOXIA produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily.
The influence on gastroprotective COX-1 activity was also assessed in a clinical study where prostaglandin synthesis was measured in gastric biopsy samples from subjects administered either ARCOXIA 120 mg daily, naproxen 500 mg twice daily, or placebo. ARCOXIA did not inhibit gastric prostaglandin synthesis as compared to placebo. In contrast, naproxen inhibited gastric prostaglandin synthesis by approximately 80% compared with placebo. These data further support the COX-2 selectivity of ARCOXIA.
Platelet Function: Multiple doses of ARCOXIA up to 150 mg administered daily up to nine days had no effect on bleeding time relative to placebo. Similarly, bleeding time was not altered in a single dose study with ARCOXIA 250 or 500 mg. There was no inhibition of ex vivo arachidonic acid- or collagen-induced platelet aggregation at steady state with doses of ARCOXIA up to 150 mg. These findings are consistent with the COX-2 selectivity of etoricoxib.
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 Cmax = 3.6 mcg/mL) was observed at approximately 1 hour (Tmax) after administration to fasted adults. The geometric mean AUC0-24hr was 37.8 mcg·hr/mL. 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. In clinical trials, etoricoxib was administered without regard to food.
The pharmacokinetics of etoricoxib in 12 healthy subjects were similar (comparable AUC, Cmax within approximately 20%) when administered alone, with a magnesium/aluminium hydroxide antacid, or a calcium carbonate antacid (approximately 50 mEq acid-neutralizing capacity).
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 mcg/mL. The volume of distribution at steady state (Vdss) is approximately 120 L in humans.
Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
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.
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: 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 an accumulation half-life of approximately 22 hours. The plasma clearance is estimated to be approximately 50 mL/min.
