Celecoxib: CYP2C9 variability influences colorectal adenoma prevention
Daniel Beylik, Pharm.D. Candidate, Class of 2016
Celecoxib is a selective COX-2 NSAID. This agent has a potentially lower incidence of gastrointestinal adverse effects as compared with nonselective COX-2 inhibitors, but has also been associated with increased risk of serious cardiovascular (CV) and thrombotic adverse events. Celecoxib is metabolized primarily through methyl hydroxylation to form hydroxyl-celecoxib, which is largely catalyzed by the CYP2C9 enzyme, although CYP3A4 also plays a minor (< 25%) role. Genetic variability in CYP2C9 is likely to have a direct impact on celecoxib pharmacokinetics and altered drug responses. Patients with certain CYP2C9 polymorphisms, specifically the *3 variant, are at increased risk of developing CV adverse events due to decreased drug metabolism and subsequent increased celecoxib levels.
Colorectal cancer risk can be mitigated through proper early detection and removal of precursor adenomatous polyps. However, suboptimal rates of screening highlight the importance of investigating chemopreventive strategies, such as NSAIDs. In the current study, investigators examined the influence of CYP2C9 variant genotypes on celecoxib dosing and subsequent risk of both adenoma and adverse events.
Chan and colleagues conducted a multicenter, randomized placebo-controlled trial that investigated the effects of celecoxib on the occurrence and incidence of endoscopically-detected adenomas. Researchers also examined the influence of CYP2C9 genetic variant genotypes on celecoxib and the risk of both adenomas and adverse events.
Patients were randomly assigned to receive placebo, low-dose (200 mg twice daily), or high-dose celecoxib (400 mg twice daily), with follow-up colonoscopies at 1 and 3 years.
There was a significant decrease in the risk of adenoma in patients possessing the CYP2C9*2 variant. In addition, both low-dose and high-dose celecoxib were associated with a significant decrease in the risk of developing adenomas with any genotype when compared with placebo.
In regards to adverse events, high-dose celecoxib demonstrated a significantly increased risk of cardiovascular adverse events in the CYP2C9*2 population. There were no significant differences in the risk of gastrointestinal hemorrhage in either celecoxib dose as compared with placebo across all genotypes.
Although this study showed a significant decrease in the risk of developing adenomas with celecoxib in select patients, routine use of celecoxib for this indication is not recommended due to a higher risk of unfavorable adverse events. In future studies, inclusion of more patients with the CYP2C9*3 polymorphism would be helpful to determine how this variant affects risk of adenoma and adverse effects.
Chan AT et al. Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma. Gastroenterol. 2009;136:2127-36.