Rofecoxib

Rofecoxib is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of rofecoxib is believed to be due to inhibition of prostaglandin synthesis, via inhibition of cyclooxygenase-2 (COX-2). At therapeutic concentrations in humans, rofecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme.

Absorption

The mean oral bioavailability of rofecoxib at therapeutically recommended doses of 12.5, 25 and 50 mg is approximately 93%. The area under the curve (AUC) and peak plasma level (C_max) following a single 25 mg dose were 3286 (±843) ng*hr/mL and 207 (±111) ng/mL, respectively. Both C_max and AUC are roughly dose proportional across the clinical dose range. At doses greater than 50 mg, there is a less than proportional increase in C_max and AUC, which is thought to be due to the low solubility of the drug in aqueous media. The plasma concentration-time profile exhibited multiple peaks. The median time to maximal concentration (T_max), as assessed in nine pharmacokinetic studies, is 2 to 3 hours. Individual T_max values in these studies ranged between 2 to 9 hours. This may not reflect rate of absorption as T_max may occur as a secondary peak in some individuals. With multiple dosing, steady state conditions are reached by Day 4. The AUC_0-24hr and C_max at steady-state after multiple doses of 25 mg rofecoxib was 4018 (±1140) ng hr/mL and 321 (±104) ng/mL, respectively. The accumulation factor based on geometric means was 1.67. Rofecoxib tablets and rofecoxib oral suspension are bioequivalent.

Food and Antacid Effects

Food had no significant effect on either the peak plasma concentration (C_max) or extent of absorption (AUC) of rofecoxib when rofecoxib tablets were taken with a high fat meal. The time to peak plasma concentration (T_max), however, was delayed by 1 to 2 hours. The food effect on the suspension formulation has not been studied. Rofecoxib tablets can be administered without regard to timing of meals.

There was a 13% and 8% decrease in AUC when rofecoxib was administered with calcium carbonate antacid and magnesium/aluminum antacid to elderly subjects, respectively. There was an approximate 20% decrease in C_max of rofecoxib with either antacid.

Distribution

Rofecoxib is approximately 87% bound to human plasma protein over the range of concentrations of 0.05 to 25 μg/mL. The apparent volume of distribution at steady state (V_dss) is approximately 91 L following a 12.5 mg dose and 86 L following a 25 mg dose.

Rofecoxib has been shown to cross the placenta in rats and rabbits, and the blood-brain barrier in rats.

Metabolism

Metabolism of rofecoxib is primarily mediated through reduction by cytosolic enzymes. The principal metabolic products are the cis-dihydro and trans-dihydro derivatives of rofecoxib, which account for nearly 56% of recovered radioactivity in the urine. An additional 8.8% of the dose was recovered as the glucuronide of the hydroxy derivative, a product of oxidative metabolism. The biotransformation of rofecoxib and this metabolite is reversible in humans to a limited extent (<5%). These metabolites are inactive as COX-1 or COX-2 inhibitors.

Cytochrome P450 plays a minor role in metabolism of rofecoxib. Inhibition of CYP3A activity by administration of ketoconazole 400 mg daily does not affect rofecoxib disposition. However, induction of general hepatic metabolic activity by administration of the non-specific inducer rifampin 600 mg daily produces a 50% decrease in rofecoxib plasma concentrations.

Excretion

Rofecoxib is eliminated predominantly by hepatic metabolism with little (<1%) unchanged drug recovered in the urine. Following a single radiolabeled dose of 125 mg, approximately 72% of the dose was excreted into the urine as metabolites, and 14% in the feces as unchanged drug.

The plasma clearance after 12.5 and 25 mg doses was approximately 141 and 120 mL/min, respectively. Higher plasma clearance was observed at doses below the therapeutic range, suggesting the presence of a saturable route of metabolism (i.e. non linear elimination). The effective half-life (based on steady state levels) was approximately 17 hours.

Special Populations

Gender

The pharmacokinetics of rofecoxib are comparable in men and women.

Geriatric

After a single dose of 25 mg rofecoxib in elderly subjects (over 65 years old) a 34% increase in AUC was observed as compared to the young subjects. Dosage adjustment in the elderly is not necessary; however, therapy with rofecoxib should be initiated at the lowest recommended dose.

Pediatric

Rofecoxib has not been investigated in patients below 18 years of age.

Race

Meta-analysis of pharmacokinetic studies has suggested a slightly (10-15%) higher AUC of rofecoxib in Blacks and Hispanics as compared to Caucasians. No dosage adjustment is necessary on the basis of race.

Hepatic Insufficiency

A pharmacokinetic study in mild (Child-Pugh score <6) hepatic insufficiency patients indicated that rofecoxib AUC was similar between these patients and healthy subjects. Limited data in patients with moderate (Child-Pugh score 7-9) hepatic insufficiency suggest a trend towards higher AUC (about 69%) of rofecoxib in these patients, but more data are needed to evaluate pharmacokinetics in these patients. Patients with severe hepatic insufficiency have not been studied.

Renal Insufficiency

In a study (N=6) of patients with end stage renal disease undergoing dialysis, peak rofecoxib plasma levels and AUC declined 18% and 9%, respectively, when dialysis occurred four hours after dosing. When dialysis occurred 48 hours after dosing, the elimination profile of rofecoxib was unchanged. While renal insufficiency does not influence the pharmacokinetics of rofecoxib, use of rofecoxib in advanced renal disease is not recommended at present because no safety information is available regarding the use of rofecoxib in these patients.