RiteMED Celecoxib Mechanism of Action

Pharmacotherapeutic Group: Antiinflammatory and antirheumatic products, non-steroids, coxibs. ATC Code: M01AH01.
Pharmacology: Pharmacodynamics: Mechanism of action: Celecoxib is an oral, selective, cyclooxygenase-2 (COX-2) inhibitor within the clinical dose range (200-400 mg daily). No statistically significant inhibition of COX-1 (assessed as ex vivo inhibition of thromboxane B2 (TxB2) formation) was observed in this dose range in healthy volunteers.
Pharmacodynamic effects: Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in human but its relevance to ulcer healing has not been established.
The difference in antiplatelet activity between some COX-1 inhibiting NSAIDs and COX-2 selective inhibitors may be of clinical significance in patients at risk of thromboembolic reactions. COX-2 selective inhibitors reduce the formation of systemic (and therefore possibly endothelial) prostacyclin without affecting platelet thromboxane.
Celecoxib is a diaryl-substituted pyrazole, chemically similar to other non-arylamine sulfonamides (e.g. thiazides, furosemide) but differs from arylamine sulfonamides (e.g. sulfamethoxazole and other sulfonamide antibiotics).
A dose-dependent effect on TxB2 formation has been observed after high doses of celecoxib. However, in healthy subjects, in small multiple dose studies with 600 mg twice daily (three times the highest recommended dose) celecoxib had no effect on platelet aggregation and bleeding time compared to placebo.
Clinical efficacy and safety: Several clinical studies have been performed confirming efficacy and safety in osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Celecoxib was evaluated for the treatment of the inflammation and pain of osteoarthritis of the knee and hip in approximately 4,200 patients in placebo- and active-controlled trials of up to 12 weeks duration. It was also evaluated for treatment of the inflammation and pain of rheumatoid arthritis in approximately 2,100 patients in placebo- and active-controlled trials of up to 24 weeks duration. Celecoxib at daily doses of 200 mg-400 mg provided pain relief within 24 hours of dosing. Celecoxib was evaluated for the symptomatic treatment of ankylosing spondylitis in 896 patients in placebo- and active-controlled trials of up to 12 weeks duration. Celecoxib at doses of 100 mg twice daily, 200 mg once daily, 200 mg twice daily and 400 mg once daily in these studies demonstrated significant improvement in pain, global disease activity and function in ankylosing spondylitis.
Five randomised, double-blind, controlled studies have been conducted including scheduled upper gastrointestinal endoscopy in approximately 4,500 patients free from initial ulceration (celecoxib doses from 50 mg-400 mg twice daily). In twelve-week endoscopy studies, celecoxib (100-800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers compared with naproxen (1,000 mg per day) and ibuprofen (2,400 mg per day). The data were inconsistent in comparison with diclofenac (150 mg per day). In two of the 12-week studies, the percentage of patients with endoscopic gastroduodenal ulceration were not significantly different between placebo and celecoxib 200 mg twice daily and 400 mg twice daily.
In a prospective long-term safety outcome study (6 to 15 months duration, the CLASS study), 5,800 osteoarthritis and 2,200 rheumatoid arthritis patients received celecoxib 400 mg twice daily (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis doses respectively), ibuprofen 800 mg three times daily or diclofenac 75 mg twice daily (both at therapeutic doses). Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (≤325 mg/day), primarily for cardiovascular prophylaxis. For the primary endpoint, complicated ulcers (defined as gastrointestinal bleeding, perforation or obstruction), celecoxib was not significantly different than either ibuprofen or diclofenac individually. Also for the combined NSAID group there was no statistically significant difference for complicated ulcers (relative risk 0.77, 95% CI 0.41-1.46, based on the entire study duration). For the combined endpoint, complicated and symptomatic ulcers, the incidence was significantly lower in the celecoxib group compared to the NSAID group, relative risk 0.66, 95% CI 0.45-0.97 but not between celecoxib and diclofenac. Those patients on celecoxib and concomitant low-dose acetylsalicylic acid experienced 4-fold higher rates of complicated ulcers as compared to those on celecoxib alone. The incidence of clinically significant decreases in haemoglobin (>2 g/dL), confirmed by repeat testing, was significantly lower in patients on celecoxib compared to the NSAID group, relative risk 0.29, 95% CI 0.17-0.48. The significantly lower incidence of this event with celecoxib was maintained with or without acetylsalicylic acid use.
In a prospective randomised 24 week safety study in patients who were aged 260 years or had a history of gastroduodenal ulcers (users of ASA excluded), the percentages of patients with decreases in haemoglobin (22 g/dL) and/or haematocrit (10%) of defined or presumed GI origin were lower in patients treated with celecoxib 200 mg twice daily (n=2,238) compared to patients treated with diclofenac sustained release 75 mg twice daily plus omeprazole 20 mg once daily (n=2,246) (0.2% vs. 1.1% for defined Gl origin, p=0.004; 0,4% vs. 2.4% for presumed GI origin, p=0.0001). The rates of clinically manifest GI complications such as perforation, obstruction or haemorrhage were very low with no differences between the treatment groups (4-5 per group).
Cardiovascular safety - long-term studies involving subjects with sporadic adenomatous polyps: Two studies involving subjects with sporadic adenomatous polyps were conducted with celecoxib i.e., the APC trial (Adenoma Prevention with Celecoxib) and the PreSAP trial (Prevention of Spontaneous Adenomatous Polyps). In the APC trial, there was a dose-related increase in the composite endpoint of cardiovascular death, myocardial infarction, or stroke (adjudicated) with celecoxib compared to placebo over 3 years of treatment. The PreSAP trial did not demonstrate a statistically significant increased risk for the same composite endpoint.
In the APC trial, the relative risks compared to placebo for a composite endpoint (adjudicated) of cardiovascular death, myocardial infarction, or stroke were 3.4 (95% CI 1.4-8.5) with celecoxib 400 mg twice daily and 2.8 (95% CI 1.1-7.2) with celecoxib 200 mg twice daily. Cumulative rates for this composite endpoint over 3 years were 3.0% (20/671 subjects) and 2.5% (17/685 subjects) respectively, compared to 0.9% (6/679 subjects) for placebo. The increases for both celecoxib dose groups versus placebo were mainly due to an increased incidence of myocardial infarction.
In the PreSAP trial, the relative risk compared to placebo for this same composite endpoint (adjudicated) was 1.2 (95% CI 0.6-2.4) with celecoxib 400 mg once daily compared to placebo. Cumulative rates for this composite endpoint over 3 years were 2.3% (21/933 subjects) and 1.9% (12/628 subjects), respectively. The incidence of myocardial infarction (adjudicated) was 1.0% (9/933 subjects) with celecoxib 400 mg once daily and 0.6% (4/628 subjects) with placebo.
Data from a third long-term study, ADAPT (The Alzheimer's Disease Anti-inflammatory Prevention Trial), did not show a significantly increased cardiovascular risk with celecoxib 200 mg twice daily compared to placebo. The relative risk compared to placebo for a similar composite endpoint (cardiovascular death, myocardial infarction, stroke) was 1.14 (95% CI 0.61-2.12) with celecoxib 200 mg twice daily. The incidence of myocardial infarction was 1.1% (8/717 patients) with celecoxib 200 mg twice daily and 1.2% (13/1,070 patients) with placebo.
Pharmacokinetics: Absorption: Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Dosing with food (high-fat meal) delays absorption by about 1 hour 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_1/2 after administration of capsule contents on applesauce.
Distribution: Plasma protein binding is about 97% at therapeutic plasma concentrations and the active substance is not preferentially bound to erythrocytes.
Biotransformation: 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 i.e., 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 metabolisers. 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 metabolisers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution (see Dosage & Administration).
No clinically significant differences were found in the PK parameters of celecoxib between elderly African-Americans and Caucasians.
The plasma concentration of celecoxib is approximately 100% increased in elderly women (>65 years).
Compared to subjects with normal hepatic function, patients with mild hepatic impairment had a mean increase in C_max of 53% and in AUC of 26% of celecoxib. The corresponding values in patients with moderate hepatic impairment were 41% and 146% respectively. The metabolic capacity in patients with mild to moderate impairment was best correlated to their albumin values. Treatment should be initiated at half the recommended dose in patients with moderate liver impairment (with serum albumin 25-35 g/L). Patients with severe hepatic impairment (serum albumin <25 g/L) have not been studied and celecoxib is contraindicated in this patient group.
There is little experience of celecoxib in renal impairment. The pharmacokinetics of celecoxib has not been studied in patients with renal impairment but is unlikely to be markedly changed in these patients. Thus caution is advised when treating patients with renal impairment. Use of celecoxib in patients with severe renal impairment is contraindicated.
Elimination: Celecoxib is mainly eliminated by metabolism. Less than 1% of the dose is excreted unchanged in urine. The inter-subject variability in the exposure to celecoxib is about 10-fold. Celecoxib exhibits dose- and time-independent pharmacokinetics in the therapeutic dose range. Elimination half-life is 8-12 hours. Steady state plasma concentrations are reached within 5 days of treatment.
Toxicology: Preclinical safety data: Non-clinical safety data revealed no special hazard for humans based on conventional studies of repeated dose toxicity, mutagenicity or carcinogenicity beyond those addressed in Precautions, Use in Pregnancy & Lactation, and Pharmacodynamics.
Celecoxib at oral doses ≥150 mg/kg/day (approximately 2-fold human exposure at 200 mg twice daily as measured by AUC0-24), caused an increased incidence of ventricular septal defects, a rare event, and foetal alterations, such as ribs fused, sternebrae fused and sternebrae misshapen when rabbits were treated throughout organogenesis, A dose-dependent increase in diaphragmatic hemias was observed when rats were given celecoxib at oral doses ≥30 mg/kg/day (approximately 6-fold human exposure based on the AUC0-24 at 200 mg twice daily) throughout organogenesis. These effects are expected following inhibition of prostaglandin synthesis. In rats, exposure to celecoxib during early embryonic development resulted in pre-implantation and post-implantation losses, and reduced embryo/foetal survival.
Celecoxib was excreted in rat milk. In a peri-post natal study in rats, pup toxicity was observed.
In a 2 year toxicity study an increase in non-adrenal thrombosis was observed in male rat at high doses.