Celebrex

[celecoxib]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Mechanism of Action:

CELEBREX is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, CELEBREX does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. In animal colon tumor models, celecoxib reduced the incidence and multiplicity of tumors.

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Pharmacokinetics:

Absorption

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 (see Food Effects). Absolute bioavailability studies have not been conducted. With multiple dosing, steady state conditions are reached on or before day 5.

The pharmacokinetic parameters of celecoxib in a group of healthy subjects are
shown in Table 1.

Table 1
Summary of Single Dose (200 mg) Disposition
Kinetics of Celecoxib in Healthy Subjects1
Mean (%CV) PK Parameter Values
Cmax, ng/mL Tmax, hr Effective t1/2, hr Vss/F, L CL/F, L/hr
705 (38) 2.8 (37) 11.2 (31) 429 (34) 27.7 (28)
1Subjects under fasting conditions (n=36, 19-52 yrs.)
Food Effects

When CELEBREX capsules were taken with a high fat meal, peak plasma levels were delayed for about 1 to 2 hours with an increase in 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 CELEBREX with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in Cmax and 10% in AUC. CELEBREX, at doses up to 200 mg BID can be administered without regard to timing of meals. Higher doses (400 mg BID) should be administered with food to improve absorption.

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