Coxicare Mechanism of Action

Pharmacology: Mechanism of Action: Etoricoxib is a member of a new class of agents called Coxibs. Etoricoxib is a potent, orally active cyclooxygenase-2 (COX-2) specific inhibitor within, and significantly 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 inhibition of platelet aggregation. 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 (within the clinical dose range) decreases these clinical signs and symptoms with decreased potential for GI toxicity and effects on platelet aggregation.
Across clinical pharmacology studies, Etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150mg daily.
The influence on gastro protective COX-1 activity was also assessed in a clinical study where prostaglandin synthesis was measured in gastric biopsy samples from subjects administered either Etoricoxib 120mg daily, naproxen 500mg twice daily, or placebo. Etoricoxib 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 Etoricoxib.
Pharmacokinetics: Absorption: Orally administered etoricoxib is well absorbed. The mean oral bioavailability is approximately 100%. Following 120mg once-daily dosing to steady state, the peak plasma concentration (geometric mean Cmax = 3.6mcg/mL) was observed at approximately 1hour (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 120mg. 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/aluminum hydroxide antacid, or a calcium carbonate antacid (approximately 50mEq acid-neutralising capacity).
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5mcg/mL. The volume of distribution at steady state (Vdss) is approximately 120L in humans.
Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Metabolism: Etoricoxib is extensively metabolised with <1% of a dose recovered in urine as the parent drug. Five metabolites have been identified in humans. Metabolism in vitro involves conversion primarily to the 6'-hydroxymethyl derivative, mainly (ca. 60%) by CYP3A4, with less contribution by CYPs 1A2, 2C9, 2C19 and 2D6 (ca. 40% collectively). The 6'-hydroxymethyl derivative is further metabolised by oxidation to the principal metabolite, the 6'-carboxylic acid derivative of etoricoxib. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.
Excretion: Following administration of a single 25mg radiolabelled intravenous dose of etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in faeces, 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 120mg, 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 50mL/min.