Rofecoxib: an update on physicochemical, pharmaceutical, pharmacodynamic and pharmacokinetic aspects

Abstract

Rofecoxib (MK-966) is a new generation non-steroidal anti-inflammatory agent (NSAID) that exhibits promising anti-inflammatory, analgesic and antipyretic activity. It selectively inhibits cyclooxygenase (COX)-2 isoenzyme in a dose-dependent manner in man. No significant inhibition of COX-1 is observed with rofecoxib up to doses of 1000 mg. The pharmacokinetics of rofecoxib has been found to be complex and variable. Mean oral bioavailability after single dose of rofecoxib (12.5, 25 or 50 mg) is 93% with t m a x varying widely between 2 and 9 h. It is highly plasma-protein bound and is metabolized primarily by cytosolic reductases to inactive metabolites. Rofecoxib is eliminated predominantly by hepatic metabolism with a terminal half-life of approximately 17 h during steady state. Various experimental models and clinical studies have demonstrated rofecoxib to be superior, or at least equivalent, in anti-inflammatory, analgesic and antipyretic efficacy to comparator nonselective NSAIDs in osteoarthritis, rheumatoid arthritis and other pain models. Emerging evidence suggests that rofecoxib may also find potential use as supportive therapy in various pathophysiologic conditions like Alzheimer's disease, and in various malignant tumours and polyps, where COX-2 is overly expressed. Rofecoxib is generally well-tolerated. Analysis of data pooled from several trials suggests that rofecoxib is associated with fewer incidences of clinically symptomatic gastrointestinal ulcers and ulcer complications vis-a Á -vis conventional NSAIDs. However, this gastropreserving effect may be negated by concurrent use of low-dose aspirin for cardiovascular risk reduction. Rofecoxib tends to show similar tolerability for renal and cardiothrombotic events as compared with nonnaproxen nonselective NSAIDs. No clinically significant drug interaction has been reported for rofecoxib except with diuretics, where it reverses their salt-wasting effect and thus can be clinically exploited in electrolyte-wasting disorders. There is only modest information about the physicochemical and pharmaceutical aspects of rofecoxib. Being poorly water soluble, its drug delivery has been improved using varied formulation approaches. Although it is stable in solid state, rofecoxib is photosensitive and base-sensitive in solution form with its degradation mechanistics elucidated. Analytical determinations of rofecoxib and its metabolites in biological fluids employing HPLC with varied types of detectors have been reported. Isolated studies have also been published on the chromatographic and spectrophotometric assay of rofecoxib and its degradants in bulk samples and pharmaceutical dosage forms. The current article provides an updated overview on the physicochemical, pharmaceutical, pharmacokinetic and pharmacodynamic vistas of rofecoxib.

Predicting Effect of Food on Extent of Drug Absorption Based on Physicochemical Properties

“…The estimated MADs of these two compounds based on the highest absorption rate suggested in the literature are much lower than the clinical dose because of very high dose number (18). However, it is reported that rofecoxib (29) and imiquimod (30) showed complete oral absorption in clinical study. The Cmax of these two compounds was also unaltered in the presence of food, suggesting lack of food effect on dissolution.…”

Rofecoxib potentiates the anticonvulsant effect of topiramate

“…But, no clinically signifi cant drug interaction has been reported for rofecoxib except that it reverses their salt-wasting effects of diuretics (Ahuja et al, 2003). Kaminski et al (1998) had earlier reported that non-steroidal anti-infl ammatory drugs (NSAIDs) increased the protective effect of valproate and phenytoin in epilepsy without altering the total plasma levels of valproate or diphenylhydantoin (Kaminski et al, 1998).…”

Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor potentiates the anticonvulsant activity of tiagabine against pentylenetetrazol-induced convulsions in mice

“…But, no clinically significant drug interaction has been reported for rofecoxib except with diuretics, where it reverses their salt-wasting effect and thus can be clinically exploited in electrolyte-wasting disorders. (Ahuja et al, 2003). Moreover, in one study done by Kaminski et al (1998), non-steroidal anti-infl ammatory agents (NSAIDs) increased the protective effect of valproate in epilepsy and when checked the plasma levels of drugs were studied, the total plasma levels of valproate and free plasma levels of diphenylhydantoin remained unchanged in the presence of all the NSAIDs examined, showing no pharmacokinetic interactions (Kaminski et al, 1998).…”