Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Non-steroidal anti-inflammatory and antirheumatic drugs, NSAIDs, 
Coxibs, ATC code: M01AH01.

Mechanism of action
Celecoxib is an oral, selective, 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 humans 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 thrombo-embolic 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. sulfamethoxizole 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 BID (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 and rheumatoid arthritis. Celecoxib was evaluated for the treatment of the inflammation and pain of osteoarthritis of the knee and hip in approximately 4200 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 2100 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.

Five randomized double-blind controlled studies have been conducted including scheduled upper gastrointestinal endoscopy in approximately 4500 patients free from initial ulceration (celecoxib doses from 50 mg – 400 mg BID). In twelve week endoscopy studies celecoxib (100 – 800 mg per day) was associated with a significantly lower risk of gastroduodenal ulcers compared with naproxen (1000 mg per day) and ibuprofen (2400 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 was not significantly different between placebo and celecoxib 200 mg BID and 400 mg BID.


In a prospective long-term safety outcome study (6-to-15-month duration, CLASS study), 5,800 osteoarthritis and 2,200 rheumatoid arthritis patients received celecoxib 400 mg BID (4-fold and 2-fold the recommended osteoarthritis and rheumatoid arthritis doses, respectively), ibuprofen 800 mg ter in die (TID) or diclofenac 75 mg BID (both at therapeutic doses). Twenty-two percent of enrolled patients took concomitant low-dose acetylsalicylic acid (≤325 mg/day), primarily         for cardiovascular (CV) 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 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 hemoglobin (>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 randomized 24 week safety study in patients who were aged ≥60 years or had a history of gastroduodenal ulcers [users of acetylsalicylic acid (ASA) excluded], the percentages of patients with decreases in hemoglobin (≥2 g/dL) and/or hematocrit (≥10 %) of defined or presumed GI origin were lower in patients treated with celecoxib 200 mg twice daily (N=2238) compared to patients treated with diclofenac SR 75 mg twice daily plus omeprazole 20 mg once daily (N=2246) (0.2 % vs.
1.1 % for defined GI 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 hemorrhage 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 and the PreSAP trial. In the APC trial, there was a dose-related increase in the composite endpoint of CV 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 CV 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 CV risk with celecoxib 200 mg BID compared to placebo.
The relative risk compared to placebo for a similar composite endpoint (CV death, myocardial infarction, stroke) was 1.14 (95 % CI 0.61 - 2.15) 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 % (13/1070 patients) with placebo.

Prospective randomized evaluation of celecoxib integrated safety vs. ibuprofen or naproxen (PRECISION)

The PRECISION study was a double-blind study of cardiovascular safety in Osteo arthritis (OA) or Rheumatoid arthritis (RA) patients with or at high risk for cardiovascular disease comparing Celecoxib (200-400 mg daily) with Naproxen (750-1000 mg daily) and Ibuprofen (1800-2400 mg daily). The primary endpoint, Antiplatelet Trialists Collaboration (APTC), was an independently adjudicated composite of cardiovascular death (including hemorrhagic death), non-fatal myocardial infarction or non-fatal stroke. The study was planned with 80% power to evaluate non-inferiority. All patients were prescribed open-label esomeprazole (20-40 mg) for gastro protection. Patients who were taking low- dose aspirin were permitted to continue therapy, at baseline nearly half of the subjects were on aspirin. Secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal outcomes. The Average Dose dispensed was 209±37 mg/day for Celecoxib, 2045±246 for Ibuprofen and 852±103 for Naproxen.

Regarding the primary endpoint, Celecoxib, as compared with either naproxen or ibuprofen, met all four pre-specified non-inferiority requirements, see Table 2.

Other independently adjudicated secondary and tertiary endpoints included cardiovascular, gastrointestinal and renal outcomes. Additionally, there was a 4-month sub study focusing on the effects of the three medicinal products on blood pressure as measured by ambulatory monitoring (ABPM).

Table 2. Primary analysis of the adjudicated APTC composite endpoint

Intent-To-Treat Analysis (ITT, through month 30)
Celecoxib     100-200    mg       Ibuprofen 600-800 mg           Naproxen 375-500 mg 
N                           8,072                             8,040                          7,969 
Subjects with Events        188 (2.3%)                        218 (2.7%)                     201 (2.5%) 
Pairwise Comparison         Celecoxib vs. Naproxen            Celecoxib vs. Ibuprofen        Ibuprofen vs. Naproxen 
HR (95% CI)                 0.93 (0.76, 1.13)                0.86 (0.70, 1.04)               1.08 (0.89, 1.31) 
Modified Intent-To-Treat Analysis (mITT, on treatment through month 43) 
Celecoxib     100-200     mg     Ibuprofen 600-800 mg            Naproxen 375-500 mg 
N                           8,030                            7,990                           7,933 
Subjects with Events        134 (1.7%)                       155 (1.9%)                      144 (1.8%) 
Pairwise Comparison         Celecoxib vs. Naproxen           Celecoxib vs. Ibuprofen         Ibuprofen vs. Naproxen 
HR (95% CI)                 0.90 (0.72, 1.14)                0.81 (0.64, 1.02)               1.12 (0.889, 1.40) 
HR – Hazard Ratio

BID – Bis in die
TID - ter in die

The results were overall numerically similar in the celecoxib and comparator groups for the secondary and tertiary endpoints and there were overall no unexpected safety findings.

Taken together the PRECISION study indicates that celecoxib at the lowest approved dose of 100 mg twice daily is non- inferior to ibuprofen dosed in the range of 600 mg-800 mg three times daily or naproxen dosed in the range of 375 mg- 500 mg twice daily with respect to cardiovascular adverse effects. The cardiovascular risks of the NSAID class, including coxibs, are dose-dependent, therefore, the results for celecoxib 200 mg daily on the composite cardiovascular endpoint cannot be extrapolated to dosing regimens using the higher doses of celecoxib.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours.
Dosing with food (high fat meal) delays absorption of celecoxib by about 1 hour resulting in a Tmax 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 Cmax, Tmax or T1/2 after administration of capsule contents on applesauce.

Distribution

Plasma protein binding is about 97% at therapeutic plasma concentrations and the medicinal product 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 Cmax and AUC0-24 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 AUC0-24 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 (see section 4.2).

No clinically significant differences were found in Pharmacokinetic parameters of celecoxib between elderly African- Americans and Caucasians.

The plasma concentration of celecoxib is approximately 100% increase in elderly women (>65 years).

Compared to subjects with normal hepatic function, patients with mild hepatic impairment had a mean increase in Cmax 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. 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 of 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.