Lexib Mechanism of Action

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs, NSAIDs, Coxibs. ATC code: M01AH01.
Pharmacology: Pharmacodynamics: The mechanism of action of celecoxib is via inhibition of prostaglandin synthesis primarily by inhibition of cyclooxygenase 2 (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 in animal models by blocking the production of inflammatory prostanoids via COX-2 inhibition. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
In vivo and ex vivo studies show that celecoxib has a very low affinity for the constitutively expressed COX-1 enzyme. 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 therapeutic plasma concentrations 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 reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism.
In a pharmacokinetic study of celecoxib 200 mg administered once daily in healthy volunteers, genotyped as either CYP2C9*1/*1, CYP2C9*1/*3, or CYP2C9*3/*3, the median C_max and AUC_0-24 of celecoxib on day 7 were approximately 4-fold and 7-fold, respectively, in subjects genotyped as CYP2C9*3/*3 compared to other genotypes. In three separate single dose studies involving a total of 5 subjects genotyped as CYP2C9*3/*3, single-dose AUC_0-24 increased by approximately 3-fold compared to normal metabolizers. It is estimated that the frequency of the homozygous *3/*3 genotype is 0.3-1.0% among different ethnic groups.
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.
Elimination: 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. Preclinical studies indicate that the drug crosses the blood-brain barrier.
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%.
In healthy adult volunteers, the overall systemic exposure (AUC) of celecoxib was equivalent when celecoxib was administered as intact capsule or capsule contents sprinkled on applesauce. There were no significant alterations in C_max, T_max or T_½ after administration of capsule contents on applesauce.
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: A meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC of celecoxib 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.
Renal impairment: In elderly volunteers 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 was comparable to those seen in patients with normal renal function. No significant relationship was found between serum creatinine (or creatinine clearance) and celecoxib clearance. Severe renal insufficiency would not be 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-PGF_1α (a prostacyclin metabolite) but leaves serum thromboxane B₂ (TXB₂) and urinary excretion of 11-dehydro-TXB₂, a thromboxane metabolite (both COX-1 products) unaffected. Specific studies have shown Celecoxib produces no decreases in GFR in the elderly or those with chronic renal insufficiency. These studies have also shown transient reductions in fractional excretion of sodium. In studies in patients with arthritis, a comparable incidence of peripheral edema has been observed to that seen with non-specific COX-inhibitors (which also possess COX-2 inhibitory activity). This was most evident in patients receiving concomitant diuretic therapy. However, increased incidences of hypertension and cardiac failure have not been observed and the peripheral edema has been mild and self-limiting.