Nonsteroidal Antiinflammatory Drugs (NSAIDs)
COX-2 inhibitors

Musculoskeletal Agents
Antiinflammatory Agents
Nonsteroidal antiinflammatory drugs (NSAIDs)

Description: Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that is a selective inhibitor of cyclooxygenase-2 (COX-2). Celecoxib demonstrates comparable efficacy to other NSAIDs (e.g., naproxen and diclofenac) in rheumatoid arthritis and osteoarthritis. Due to celecoxib's specificity for the COX-2 cyclooxygenase pathway, it has the potential to cause less gastropathy and risk of GI bleeding; more data are needed. All NSAIDs including celecoxib cause an increased risk of serious gastrointestinal (GI) adverse effects including bleeding, ulceration, and perforation of the stomach or intestines and may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke. The lowest effective celecoxib dose for the shortest possible duration is recommended, as the risk for adverse effects may increase with duration of use. Although it has been hypothesized that COX-1 cyclooxygenase antagonism may contribute to the renal adverse effects of NSAIDs, clinical trials have shown similar renal effects with celecoxib and NSAIDs. Celecoxib was approved by the FDA in December 1998 under priority review to relieve the signs and symptoms of rheumatoid arthritis and osteoarthritis. In August 2005, celecoxib received FDA approval for the treatment of ankylosing spondylitis. Under the priority review process, the FDA approved celecoxib as adjuvant treatment for patients with familial adenomatous polyposis (FAP) in December 1999; treatment with celecoxib reduced the number of adenomatous colorectal polyps by an average of 28% as compared to only 5% with placebo. Over a 3-year period, celecoxib significantly reduced the development of colorectal adenomas in patients without FAP but with a history of a colorectal adenoma(s), but the effect of celecoxib on colorectal cancer prevention is unknown, and celecoxib use increased the risk of serious cardiovascular events as compared with placebo.[9482] [9483] On December 15, 2006, the FDA approved the use of celecoxib to treat the signs and symptoms of juvenile rheumatoid arthritis (JRA) in children 2 years of age and older. Safety and efficacy of the drug in JRA beyond 6 months of use has not been established; however postmarketing studies will be conducted to assess the long term effects of the drug on renal toxicity, hypertension, and cardiovascular events.

Mechanism of Action: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzyme cyclooxygenase (COX). There are 2 isoenzymes of COX, COX-1 and COX-2. With its polar sulfonamide side chain, celecoxib binds tightly to a distinct hydrophilic side pocket region of COX-2, which is close in proximity to the active binding site. The COX-2 specificity is due to this ability of celecoxib to occupy space within the active binding site that is not present on the COX-1 isoform. The isoenzymes COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin G2 (PGG2), the first step in the synthesis prostaglandins and thromboxanes that are involved in rapid physiological responses. COX isoenzymes are also responsible for a peroxidase reaction, which is not affected by NSAIDs. In addition, NSAIDs do not suppress leukotriene synthesis by lipoxygenase pathways. The isoenzyme COX-1 produces thromboxane A2 whereas the isoenzyme COX-2 produces prostaglandin I2 (PGI2). Selective inhibition of the COX-2 enzyme results in analgesic, antipyretic, and anti-inflammatory pharmacologic effects. Due to its selective COX-2 inhibitory activity, celecoxib does not inhibit platelet aggregation as seen with aspirin or other non-selective NSAIDs (see Cardiovascular Effects). COX-1 is constitutively expressed in almost all tissues, while COX-2 appears to only be constitutively expressed in the brain, kidney, bones, reproductive organs, and some neoplasms (e.g., colon and prostate cancers). COX-1 is responsible for prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis. However, COX-2 is inducible in many cells in response to certain mediators of inflammation (e.g., interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates).
•Anti-inflammatory Activity: The anti-inflammatory mechanism of celecoxib is due to decreased prostaglandin synthesis via inhibition of COX-2. Although anti-inflammatory effects may be primarily due to inhibition of the COX-2 isoenzyme, COX-1 is expressed at some sites of inflammation. COX-1 is expressed in the joints of rheumatoid arthritis or osteoarthritis patients, especially the synovial lining, and it is the primary enzyme of prostaglandin synthesis in human bursitis. Celecoxib is considered to be a selective COX-2 inhibitor. The in vitro selectivity of COX-2 inhibition (COX-1:COX-2 IC50) as determined by whole blood assay for celecoxib is 6.5—7.5 as compared to diclofenac 3.0, etodolac 2.4, and meloxicam 2.0 (NOTE: A higher number indicates greater COX-2 selectivity).[2760] [4086]
•Analgesic Activity: Celecoxib is effective in cases where inflammation has caused sensitivity of pain receptors (hyperalgesia). It appears prostaglandins, specifically prostaglandins E and F, are responsible for sensitizing the pain receptors; therefore, celecoxib has an indirect analgesic effect by inhibiting the production of further prostaglandins and does not directly affect hyperalgesia or the pain threshold.
•Chemoprevention Activity: Many neoplasms overexpress COX-2 messenger RNA and COX-2 protein suggesting a contributory role for COX-2 in carcinogenesis. Mechanisms of COX-2 in tumorigenesis include conversion of procarcinogens to active carcinogens, stimulation of cancer cell proliferation, inhibition of apoptosis, increased invasiveness, and enhancement of angiogenesis. Expression of COX-2 by colorectal cancers has been associated with a poor prognosis, decreased survival, and advanced Dukes tumor stage.[2639] Celecoxib has been shown to reduce the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis (FAP). Celecoxib is also being studied in combination with chemotherapy in the treatment of colorectal cancer. Preliminary results suggest that celecoxib may increase the response rate seen with standard chemotherapy.
•Gastrointestinal Effects: Although COX-2 selective inhibitors were developed in hopes of avoiding the GI toxicity associated with non-selective NSAIDs, GI adverse reactions do occur with these agents, albeit at lower rate. The role of COX-2 in tissue repair processes, in H. pylori infections and other ulcers where its expression is increased, in tolerance of dietary antigens, and in colitis has yet to be determined.
•Renal Effects: In the kidney, prostaglandins produced by both COX-1 and COX-2, are important regulators of sodium and water reabsorption through PGE2 and of renal function and hemodynamics via PGI2 in response to vasoconstrictive factors (e.g., endothelin-1, a factor that increases peripheral vascular resistance) and through effects on the renin-angiotensin system. Activity of COX-2 in the renal cortex appears to be inhibited by angiotensin II and stimulated by intravascular volume depletion and low sodium intake. The COX-2 isoenzyme is constitutively expressed in the kidney. In response to decreased intravascular volume, COX-2 activation leads to prostaglandin production. Maintenance of an adequate intravascular volume is achieved by prostaglandin synthesis and subsequent renin release through angiotensin II and aldosterone generation. If prostaglandin production is inhibited by a NSAID regardless of COX 2 selectivity, renal blood flow is reduced. Consequently, antidiuretic hormone (ADH) production and sodium reabsorption are increased, which leads to a reduction in glomerular filtration rate, reduced urinary sodium excretion, and the potential for increased blood pressure. Glomerular filtration rate reduction of elderly or salt-depleted patients after administration of a COX 2 inhibitor has been demonstrated in several trials.[4732] [4733] [4734] In conditions where renal blood flow is dependent upon prostaglandin synthesis, administration of NSAIDs can result in significant decreases in renal blood flow leading to acute renal failure.
•Cardiovascular Effects: Selective inhibition of COX-2 will inhibit the production of PGI2 but not of thromboxane A2, which is produced by COX-1. Thromboxane A2 causes platelet aggregation, vasoconstriction, and vascular proliferation whereas PGI2 inhibits platelet aggregation, vascular smooth muscle contraction and proliferation, leukocyte endothelial cell interactions, and cholesteryl ester hydrolysis. As PGI2 inhibits platelet aggregation, prevention of its production in the presence of an inducer of platelet aggregation (thromboxane A2) may create an imbalance favoring a pro-thrombotic state (see Adverse Effects). Also, inhibition of PGI2 could lead to sodium and water retention, which may increase blood pressure, or worsen heart failure or other cardiovascular morbidity (see Renal Effects). The presence of the thromboxane metabolite, 2,3-dinor thromboxane B2, in urine reflects platelet activation, and platelet activation facilitates atherogenesis.[7455] The amount of thromboxane metabolite excretion was higher in male as compared with female mice deficient in LDL receptors. Interestingly, excretion of the thromboxane metabolite by female mice deficient in both LDL and PGI2 receptors exceeded the amount excreted by male mice deficient in both receptors. Thus, in female mice, PGI2 decreases platelet activation. Furthermore, PGI2 appears to reduce oxidative stress only in female mice by serving as an antioxidant. In female mice deficient in both LDL and PGI2 receptors, lipid peroxidation was increased as compared with female mice deficient only in LDL receptors. Male mice deficient in both receptors did not have further lipid peroxidation as compared with male mice deficient only in LDL receptors. In vitro, estrogen has been shown to increase the expression of COX-2 in vascular tissues and to augment PGI2 production. Despite the differences between men and women in regard to age-dependent increases in cardiovascular disease, the mechanisms of atheroprotection in women before the menopause are largely unknown. In mice, estrogen, by acting on estrogen receptor subtype alpha, upregulates prostacyclin (PGI2) production by COX-2 activation.[7455]

Pharmacokinetics: Celecoxib is administered orally. Celecoxib is well absorbed, with peak plasma levels of celecoxib occurring approximately 3 hrs after an oral dose. Both peak plasma levels (Cmax) and area under the curve (AUC) are roughly dose proportional across the clinical dose range of 100—200 mg studied. At higher doses and under fasting conditions, there is a less than proportional increase in Cmax and AUC which is thought to be due to the low aqueous solubility of the drug. Absolute bioavailability studies have not been conducted. When celecoxib capsules are taken with a high fat meal, peak plasma levels are delayed for about one to two hours with an increase in total absorption (AUC) of 10—20%; however, this effect is not significant.

Celecoxib is widely distributed and highly bound to plasma proteins (~97%), primarily to albumin and, to a lesser extent, alpha-1-acid glycoprotein. The apparent steady-state volume of distribution is approximately 400 L. Celecoxib is not preferentially bound to red blood cells.

Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three inactive metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previous history may have reduced metabolic clearance of celecoxib.

Celecoxib is eliminated predominantly by hepatic metabolism (> 97%) with little unchanged drug recovered in the urine and feces. The metabolites are eliminated by the biliary and renal route; 57% of the total dose is recovered in the feces and 27% recovered in the urine. The apparent plasma clearance is about 500 ml/min. The mean effective half-life is 11.2 (31% CV) hours under fasted conditions. The low solubility of the drug prolongs the absorption process, making terminal half-life (T 1/2) determinations variable.

Impaired renal or hepatic function, advanced age, and race are associated with statistically significant changes in the pharmacokinetics of celecoxib. In patients with chronic renal insufficiency (GFR 35—60 mL/min), celecoxib AUC is approximately 40% lower than in subjects with normal renal function; celecoxib clearance did not correlate with GFR. Patients with severe renal insufficiency have not been studied. In mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, steady-state celecoxib AUC is increased about 40% and 180%, respectively, above that seen in healthy subjects. Patients with severe hepatic insufficiency have not been studied. Elderly subjects (over 65 years old) have a 40% higher Cmax and a 50% higher AUC compared to young subjects. In elderly females, celecoxib Cmax and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. A meta-analysis of pharmacokinetic studies found the AUC of celecoxib to be 40% higher in Blacks compared to Caucasians; the clinical significance is unknown.

2639. Sheehan KM, Sheahan K, O'Donoghue DP, et al. The relationship between cylooxgenase-2 Expression and colorectal cancer. JAMA 1999;282:1254—7.

2760. Chan CC, Boyce S, Brideau C, et al. Rofecoxib Vioxx, MK-0966; [4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. J Clin Pharmacol Exp Ther 1999;290:551—60.

4086. Riendeau D, Percival MD, Brideau C, et al. Etoricoxib (MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther 2001;296:558—566.

4732. Rossat J, Maillard M, Nussberger J, et al. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 1999;66:76—84.

4733. Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med 2000;160:1465—70.

4734. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet: a randomized, controlled trial. Ann Intern Med 2000;133:1—9.

7455. Karine M. Egan KM, Lawson JA, Fries S, et al. COX-2-Derived prostacyclin confers atheroprotection on female mice. Science 2004;306:1954—57.

9482. Bertagnolli MM, Eagle CJ, Zauber AG, et al. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med 2006;355:873—84.

9483. Arber NA, Eagle CJ, Spicak J, et al. Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006;355:885—95.

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