Arcoxia/Arcoxia Ac Mechanism of Action

Pharmacology: Pharmacokinetics: Absorption: 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 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, C_max within approximately 20%) when administered alone, with a magnesium/aluminum 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 (V_dss) 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.
Characteristics in Patients (Special Populations): Gender: The pharmacokinetics of etoricoxib are similar between men and women. (See Dosage & Administration.)
Elderly: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young. No dosage adjustment is necessary for elderly patients. (See Dosage & Administration.)
Race: There is no clinically important effect of race on the pharmacokinetics of etoricoxib. (See Dosage & Administration.)
Hepatic Insufficiency: Patients with mild hepatic insufficiency (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 insufficiency (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 insufficiency (Child-Pugh score >9). (See Hepatic Insufficiency under Dosage & Administration.)
Renal Insufficiency: 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 of age) have not been studied.
In a pharmacokinetic study (N=16) conducted in adolescents (aged 12 to 17) the pharmacokinetics in adolescents weighing 40 to 60 kg given etoricoxib 60 mg once daily and in 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.
Drug Interactions with additional pharmacokinetic data: The main pathway of etoricoxib biotransformation is CYP-dependent oxidation to produce 6'-hydroxymethyl etoricoxib, which can undergo further metabolism to the corresponding carboxylic acid or O-glucuronide. In vitro data indicate that CYP3A4 plays a major role (approximately 60%) in the hydroxylation of etoricoxib and that the remainder of the activity (approximately 40%) is shared among CYP2C9, 1A2, 2C19, and 2D6. Administration of a potent inhibitor of CYP3A4 (ketoconazole) did not increase etoricoxib plasma concentrations to a clinically meaningful extent (approximate 43% increase in AUC). Administration of a potent inducer of CYP enzymes (rifampin) produced a 65% decrease in etoricoxib plasma AUC.
The potential for etoricoxib to inhibit or induce CYP3A4 activity was investigated in human studies using the intravenous erythromycin breath test. Compared to placebo, etoricoxib (120 mg daily for 11 days) did not produce any significant effect on erythromycin N-demethylation, indicating no effect on hepatic CYP3A4 activity. Based on in vitro studies, etoricoxib does not inhibit cytochromes P450 1A2, 2C9, 2C19, 2D6, or 2E1.