Pharmacology: Pharmcodynamics: Mechanism of Action:
Celecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, celecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.
Platelets: No effect on reduction of platelet aggregation or increase in bleeding time has been reported with celecoxib at single doses up to 800 mg and multiple doses of 600 mg twice daily for up to 7 days duration (higher than recommended therapeutic doses).
Because of its lack of platelet effects, celecoxib is not a substitute for aspirin for cardiovascular prophylaxis. It is not known if there are any effects of celecoxib on platelets that may contribute to the increased risk of serious cardiovascular thrombotic adverse events associated with the use of celecoxib.
Fluid Retention: Inhibition of PGE2
synthesis may lead to sodium and water retention through increased reabsorption in the renal medullary thick ascending loop of Henle and perhaps other segments of the distal nephron. In the collecting ducts, PGE2
appears to inhibit water reabsorption by counteracting the action of antidiuretic hormone.
Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Under fasting conditions, both peak plasma levels (Cmax
) and area under the curve (AUC) are roughly dose-proportional up to 200 mg BID; at higher doses there are less than proportional increases in Cmax
and AUC. With multiple dosing, steady-state conditions are reached on or before Day 5. The pharmacokinetic parameters of celecoxib in healthy subjects are shown in table. (See Table 1.)
Click on icon to see table/diagram/image
When celecoxib capsules were taken with a high fat meal, peak plasma levels were reported to be delayed for about 1 to 2 hours with an increase into total absorption (AUC) of 10% to 20%. Under fasting conditions, at doses above 200 mg, there is less than a proportional increase in Cmax
and AUC, which is thought to be due to the low solubility of the drug in aqueous media.
Coadministration of celecoxib with an aluminum- and magnesium-containing antacids resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax
and 10% in AUC. Celecoxib, at doses up to 200 mg twice daily, can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption.
Celecoxib is highly protein bound (~97%) within the clinical dose range. Celecoxib has been reported to bind primarily to albumin and, to a lesser extent, α1
acid glycoprotein. The apparent volume of distribution at steady state (Vss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentially bound to red blood cells.
Celecoxib metabolism is primarily mediated via CYP2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors.
Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 57% of the dose was reported to be excreted in the feces and 27% into the urine. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. It appears that the low solubility of the drug prolongs the absorption process making terminal half-life (t½
) determinations more variable. The effective half-life is approximately 11 hours under fasted conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.
CYP2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*2 and CYP2C9*3 polymorphisms. Limited data from published reports that included a total of 8 subjects with the homozygous CYP2C9*3/*3 genotype showed celecoxib systemic levels that were 3- to 7-fold higher in these subjects compared to subjects with CYP2C9*1/*1 or *I/*3 genotypes. The pharmacokinetics of celecoxib have not been reported in subjects with other CYP2C9 polymorphisms, such as *2, *5, *6, *9 and *11. It is estimated that the frequency of the homozygous *3/ *3 genotype is 0.3% to 1.0% in various ethnic groups (see Dosage & Administration and Use in Special Populations under Precautions).
At steady state, elderly subjects (over 65 years old) had reported a 40% higher Cmax
and a 50% higher AUC compared to the 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. Dose adjustment in the elderly is not generally necessary. However, for patients of less than 50 kg in body weight, initiate therapy at the lowest recommended dose (see Dosage & Administration and Precautions).
The oral clearance (unadjusted for body weight) of celecoxib has been reported to increase less than proportionally to increasing weight, with 10 kg and 25 kg patients predicted to have 40% and 24% lower clearance, respectively, compared with a 70 kg adult RA patient.
An approximately 40% higher AUC of celecoxib has been reported in Blacks compared to Caucasians. The cause and clinical significance of this finding is unknown.
The steady-state celecoxib AUC is reported to increase by about 40% and 180%, in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, respectively. Therefore, the daily recommended dose of celecoxib capsules should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied. The use of celecoxib in patients with severe hepatic impairment is not recommended (see Dosage & Administration and Precautions).
The celecoxib AUC is approximately 40% lower in patients with chronic renal insufficiency (GFR 35-60 mL/min) than in subjects with normal renal function. No significant relationship has been reported between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied. Similar to other NSAIDs, celecoxib is not recommended in patients with severe renal insufficiency (see Precautions).