Myox Mechanism of Action

Pharmacology: Pharmacodynamics: Etoricoxib is a non-steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities. It selectively inhibits cyclooxygenase-2 (COX-2) isoenzymes, resulting in inhibition of prostaglandin synthesis. At therapeutic doses, etoricoxib does not inhibit COX-1 isoenzyme. Thus, it does not interfere with the normal COX-1 related physiological processes in tissues, such as the gastric prostaglandin synthesis, and had no effect on platelet function. Etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily.
Pharmacokinetics: Etoricoxib is well absorbed after oral administration, with an absolute bioavailability of approximately 100%. Peak plasma concentrations occur in about 1 hour following administration in fasted adults. The pharmacokinetics of etoricoxib is linear across clinical dose range. The onset of action of etoricoxib can occur as early as 24 minutes following administration. Dosing of etoricoxib 120 mg with food (i.e., high-fat meal) decreased the peak plasma concentrations (C_max) by 36% and increased the time to reach peak plasma concentrations (t_max) by 2 hours; however, it did not alter the extent of absorption of etoricoxib.
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) of etoricoxib was approximately 120 L in humans. It was demonstrated that etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Etoricoxib is extensively metabolized; only less than 1% of the administered drug was recovered in the urine as the parent drug. Five metabolites have been identified in man. The major route of metabolism is via cytochrome P450 (CYP) enzymes to form the 6'-hydroxymethyl derivative, which is then oxidized to the 6'-carboxylic acid derivative, the principal metabolite. These principal metabolites are both inactive or only weak COX-2 inhibitors, while none of these metabolites demonstrated COX-1 inhibition.
In vivo studies demonstrated that CYP3A4 appears to mainly contribute to the metabolism of etoricoxib, while CYP2D6, CYP2C9, CYP1A2 and CYP2C19 can catalyze the main metabolic pathway in vitro, but their quantitative roles in vivo have not been studied.
Steady state concentrations are attained with the administration of etoricoxib 120 mg once daily for 7 days, with an accumulation ratio of approximately 2, corresponding to a half-life of about 22 hours. The plasma clearance after the intravenous administration of etoricoxib 25 mg is estimated to be approximately 50 mL/min. Etoricoxib is mainly excreted through the kidneys. Following the intravenous administration of a single 25 mg radiolabeled 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.
Special Populations: Hepatic Impairment: The administration of etoricoxib 60 mg once daily in patients with mild hepatic dysfunction (Child-Pugh score 5 to 6) increased the mean area under the concentration-time curve (AUC) by 16% when compared to healthy subjects. Patients with moderate hepatic dysfunction (Child-Pugh score 7 to 9) administered with etoricoxib 60 mg every other day had similar mean AUC to the healthy subjects who received the same dose of etoricoxib once daily. There are no clinical or pharmacokinetic data performed in patients with severe hepatic dysfunction (Child-Pugh ≥10).
Renal Impairment: 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 with a dialysis clearance of approximately 50 mL/min has a negligible effect in the elimination of etoricoxib.
Elderly: The pharmacokinetics of etoricoxib in patients 65 years and older are similar to those in young patients.
Children: The pharmacokinetics of etoricoxib 60 mg administered once daily in adolescents 12 to 17 years old weighing 40 to 60 kg and of etoricoxib 90 mg given once daily in adolescents weighing >60 kg were similar to the pharmacokinetics in adults administered with etoricoxib 90 mg once daily. The pharmacokinetics of etoricoxib in children 12 years old and younger have not been studied.