Celxib 200 Mechanism of Action

MIMS Classification(s): Non-steroidal Anti-inflammatory Agent (NSAID).
Pharmacology: The mechanism of action of Celecoxib is via inhibition of prostaglandin synthesis primarily by inhibition of COX-2. At therapeutic concentrations in humans, Celecoxib does not inhibit cyclooxygenase 1 (COX-1). COX-2 is induced in response to inflammatory stimuli. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular prostaglandin E2, causing inflammation, edema and pain. Celecoxib acts as an anti-inflammatory, analgesic, and antipyretic agent by blocking the production of inflammatory prostanoids via COX-2 inhibition.
Consequently at therapeutic doses Celecoxib has no effect on prostanoids synthesized by activation of COX-1 thereby not interfering with normal COX-1 related physiological processes in tissues, particularly the stomach, intestine and platelets.
Pharmacokinetics: Absorption: When given under fasting conditions, Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Oral bioavailability from capsules is about 99% relative to administration in suspension (optimally available oral dosage form). Under fasting conditions, both peak plasma levels (C_max) and area under the curve (AUC) are roughly dose proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in C_max and AUC.
Distribution: Plasma protein binding, which is concentration independent, is about 97% at the therapeutic plasma concentration and Celecoxib is not preferentially bound to erythrocytes in the blood.
Metabolism: Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human plasma: a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate.
Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduce enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism.
Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered Celecoxib with caution. Consider starting treatment at half the lowest recommended dose (see Dosage & Administration, and Interactions).
Excretion: Elimination of Celecoxib is mostly by hepatic metabolism with less than 1% of the dose excreted unchanged in urine. After multiple dosing, elimination half-life is 8 to 12 hours and the rate of clearance is about 500 mL/min. With multiple dosing steady-state plasma concentrations are reached before day 5. The intersubject variability on the main pharmacokinetic parameters (AUC, C_max, elimination half-life) is about 30%. The mean steady-state volume of distribution is about 500 L/70 Kg in young healthy adults indicating wide distribution of Celecoxib into the tissues.
Food effects: Dosing with food (high fat meal) delays absorption of Celecoxib resulting in a T_max of about 4 hours and increases bioavailability by about 20% (see Dosage & Administration).
Special Populations: Elderly: In the population > 65 years there is a one and a half to two-fold increase in mean C_max and AUC for Celecoxib. This is a predominantly weight-related rather than age-related change. Celecoxib levels being higher in lower weight individuals and consequently higher in the elderly population who are generally of lower mean weight than the younger population. Therefore, elderly females tend to have higher drug plasma concentrations than elderly males. No dosage adjustment is generally necessary. However, for elderly patients with a lower than average body weight (< 50 Kg), initiate therapy at the lowest recommended dose.
Race: An approximately 40% AUC of Celecoxib is higher in the Black population compared to Caucasians. The cause and clinical significance of this finding is unknown.
Hepatic impairment: Plasma concentrations of Celecoxib in patients with mild hepatic impairment (Child-Pugh Class A) are not significantly different from those of age and sex matched controls. In patients with moderate hepatic impairment (Child-Pugh Class B) Celecoxib plasma concentrations are about twice those of matched controls (see Dosage & Administration).
Renal impairment: In the elderly with age-related reductions in glomerular filtration rate (GFR) (mean GFR > 65 mL/min 1.73 m²) and in patients with chronic stable renal insufficiency (GFR 35-60 mL/min/1.73 m²). Celecoxib pharmacokinetics is comparable to those seen in patients with normal renal function. No significant relationship can be found between serum creatinine (or creatinine clearance) and Celecoxib clearance. Severe renal insufficiency is expected to alter clearance of Celecoxib since the main route of elimination is via hepatic metabolism to inactive metabolites.
Renal effects: The relative roles of COX-1 and COX-2 in renal physiology are not completely understood. Celecoxib reduces the urinary excretion of PGE2 and 6-keto-PGF1 (a prostacyclin metabolite) but leaves serum thromboxane B₂ (TXB₂) and urinary excretion of 11-dehydro-TXB₂, a thromboxane metabolite (both COX-1 products) unaffected. Celecoxib produces no decreases in GFR in the elderly or those with chronic renal insufficiency. It will also show transient reductions in fractional excretion of sodium.