Valdecoxib

Valdecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic properties in animal models. The mechanism of action is believed to be due to inhibition of prostaglandin synthesis primarily through inhibition of cyclooxygenase-2 (COX-2). At therapeutic plasma concentrations in humans valdecoxib does not inhibit cyclooxygenase-1 (COX-1).

Absorption

Valdecoxib achieves maximal plasma concentrations in approximately 3 hours. The absolute bioavailability of valdecoxib is 83% following oral administration of valdecoxib compared to intravenous infusion of valdecoxib.

Dose proportionality was demonstrated after single doses (1-400 mg) of valdecoxib. With multiple doses (up to 100 mg/day for 14 days), valdecoxib exposure as measured by the AUC, increases in a more than proportional manner at doses above 10 mg BID. Steady state plasma concentrations of valdecoxib are achieved by day 4.

The steady state pharmacokinetic parameters of valdecoxib in healthy male subjects are shown in Table 1.

Table 1. Mean (SD) Steady State Pharmacokinetic Parameters:

No clinically significant age or gender differences were seen in pharmacokinetic parameters that would require dosage adjustments. Effect of Food and Antacid

Valdecoxib can be taken with or without food. Food had no significant effect on either the peak plasma concentration (C_max) or extent of absorption (AUC) of valdecoxib when valdecoxib was taken with a high fat meal. The time to peak plasma concentration (T_max), however, was delayed by 1-2 hours. Administration of valdecoxib with antacid (aluminum/magnesium hydroxide) had no significant effect on either the rate or extent of absorption of valdecoxib.

Distribution

Plasma protein binding for valdecoxib is about 98% over the concentration range (21-2384 ng/mL). Steady state apparent volume of distribution (Vss/F) of valdecoxib is approximately 86 L after oral administration. Valdecoxib and its active metabolite preferentially partition into erythrocytes with a blood to plasma concentration ratio of about 2.5:1. This ratio remains approximately constant with time and therapeutic blood concentrations.

Metabolism

In humans, valdecoxib undergoes extensive hepatic metabolism involving both P450 isoenzymes (3A4 and 2C9) and non-P450 dependent pathways (i.e., glucuronidation). Concomitant administration of valdecoxib with known CYP 3A4 and 2C9 inhibitors (e.g., fluconazole and ketoconazole) can result in increased plasma exposure of valdecoxib.

One active metabolite of valdecoxib has been identified in human plasma at approximately 10% the concentration of valdecoxib. This metabolite, which is a less potent COX-2 specific inhibitor than the parent, also undergoes extensive metabolism and constitutes less than 2% of the valdecoxib dose excreted in the urine and feces. Due to its low concentration in the systemic circulation, it is not likely to contribute significantly to the efficacy profile of valdecoxib.

Excretion

Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-glucuronide. The apparent oral clearance (CL/F) of valdecoxib is about 6 L/hr. The mean elimination half-life (T_1/2) ranges from 8-11 hours, and increases with age.

Special Populations

Geriatric

In elderly subjects (>65 years), weight-adjusted steady state plasma concentrations (AUC_(0-12hr)) are about 30% higher than in young subjects. No dose adjustment is needed based on age.

Pediatric

Valdecoxib has not been investigated in pediatric patients below 18 years of age. h4. Race

Pharmacokinetic differences due to race have not been identified in clinical and pharmacokinetic studies conducted to date.

Hepatic Insufficiency

Valdecoxib plasma concentrations are significantly increased (130%) in patients with moderate (ChildPugh Class B) hepatic impairment. In clinical trials, doses of valdecoxib above those recommended have been associated with fluid retention. Hence, treatment with valdecoxib should be initiated with caution in patients with mild to moderate hepatic impairment and fluid retention. The use of valdecoxib in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended.

Renal Insufficiency

The pharmacokinetics of valdecoxib have been studied in patients with varying degrees of renal impairment. Because renal elimination of valdecoxib is not important to its disposition, no clinically significant changes in valdecoxib clearance were found even in patients with severe renal impairment or in patients undergoing renal dialysis. In patients undergoing hemodialysis the plasma clearance (CL/F) of valdecoxib was similar to the CL/F found in healthy elderly subjects (CL/F about 6 to 7 L/hr.) with normal renal function (based on creatinine clearance).

NSAIDs have been associated with worsening renal function and use in advanced renal disease is not recommended.