Arcoxia Mechanism of Action



Merck Sharp & Dohme


Transfarma Medica Indah
Full Prescribing Info
Arcoxia (etoricoxib) is a member of a class of arthritis/analgesia medications called coxibs. It 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 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 eg, 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 9 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: 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 hr (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.
In studies specifically designed to measure the onset of action of etoricoxib, the onset of action occurred as early as 29 min after dosing.
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 regards 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 50 mEq acid-neutralizing capacity).
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05-5 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 P-450 (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 IV 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 7 days of once-daily administration of 120 mg, with an accumulation ratio of approximately 2, corresponding to an accumulation t½ of approximately 22 hrs. 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) 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. There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9). (See 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) have not been studied.
In a pharmacokinetic study (N=16) conducted in adolescents (12-17 years) the pharmacokinetics in adolescents weighing 40-60 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.
Toxicology: Acute Toxicity: The approximate oral LD50 was 1499 mg/kg in both female mice and rats, while the intraperitoneal approximate oral LD50 was 599 mg/kg in female mice and 238 mg/kg in female rats. The approximate oral LD50 in rats and mice are >12 times the acute daily adult human dose (120 mg) based on systemic exposure.
Chronic Toxicity: The toxicity potential of etoricoxib was evaluated in a series of repeated-dose oral toxicity studies up to 53 weeks in dogs and rats. In each species, the principal treatment-related changes were associated with renal and gastrointestinal toxicity. Both the renal and gastrointestinal lesions were shown to occur at dosages above the intended chronic clinical dose of 90 mg daily.
In dogs, etoricoxib administered orally at dosages of 200 mg/kg/day (approximately 20 times the daily adult human dose [90 mg] based on systemic exposure) for 14 weeks, toxicity was characterized by gastritis, gastrointestinal ulceration and renal papillary necrosis. No toxicity was seen in dogs administered 50 mg/kg/day (approximately 3 times the daily adult human dose based on systemic exposure) for 53 weeks.
In rats, etoricoxib administered orally at dosages of 30 mg/kg/day (approximately 3 times the daily adult human dose [90 mg] based on systemic exposure) following 27 weeks of administration produced gastrointestinal ulceration, as well as increased hepatic weights in female rats. At 53 weeks, the increased hepatic weights observed correlated with centrilobular hepatocellular hypertrophy due to hepatic CYP enzyme induction. No renal or gastrointestinal changes were noted in rats administered 10 mg/kg/day for 53 weeks (approximately equivalent to the daily adult human dose based on systemic exposure).
Teratogenicity: No teratogenic effects were observed in rabbits and rats administered etoricoxib at doses up to 10 mg/kg/day and 15 mg/kg/day, respectively (approximately equal to and approximately 1.5 times, respectively, the daily adult human dose [90 mg] based on systemic exposure).
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