DrugLib.com — Drug Information Portal

Rx drug information, pharmaceutical research, clinical trials, news, and more



Cytochrome P450 2C9 variants influence response to celecoxib for prevention of colorectal adenoma.

Author(s): Chan AT, Zauber AG, Hsu M, Breazna A, Hunter DJ, Rosenstein RB, Eagle CJ, Hawk ET, Bertagnolli MM

Affiliation(s): Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. achan@partners.org

Publication date & source: 2009-06, Gastroenterology., 136(7):2127-2136.e1. Epub 2009 Feb 21.

Publication type: Comparative Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

BACKGROUND & AIMS: Variants in the cytochrome P450 2C9 (CYP2C9) gene are associated with impaired metabolism of celecoxib. We examined the influence of CYP2C9*2 (R144C) and CYP2C9*3 (I359L) variants on dose-related response or toxicity in a randomized trial of celecoxib. METHODS: We identified individuals with CYP2C9*2 and CYP2C9*3 genotypes (>or=1 variant allele) in the Adenoma Prevention with Celecoxib trial. Following adenoma removal, patients were assigned randomly to groups given placebo or low-dose (200 mg twice daily) or high-dose (400 mg twice daily) celecoxib and underwent follow-up colonoscopies at 1 and/or 3 years. RESULTS: Among 1660 patients, 21% were CYP2C9*2, and 12% were CYP2C9*3 genotypes. Overall, celecoxib was associated with a dose-dependent reduction in adenoma, compared with placebo, with relative risks (RR) of 0.65 (95% confidence interval [CI]: 0.56-0.76) for the low-dose and 0.54 (95% CI: 0.46-0.63) for the high-dose groups. However, the additional protective effect of the high dose, compared with the low-dose, was observed only in those with CYP2C9*3 genotypes (RR, 0.51; 95% CI: 0.30-0.87). The high dose, compared with low dose, was not associated with significant risk reduction among those with CYP2C9*2 (RR, 0.83; 95% CI: 0.57-1.21) or wild-type (RR, 0.89; 95% CI: 0.72-1.11) genotypes. Compared with placebo, a higher incidence of cardiovascular events was associated with both doses among patients with wild-type genotypes but only with the high dose among patients with variant genotypes. CONCLUSIONS: The greater efficacy of high-dose celecoxib, compared with the low-dose, in preventing colorectal adenoma appears confined to individuals with slow metabolizer (CYP2C9*3) genotypes. Genetic variability influences susceptibility to the potential benefits and hazards of celecoxib.

Page last updated: 2009-10-20

-- advertisement -- The American Red Cross
 
Home | About Us | Contact Us | Site usage policy | Privacy policy

All Rights reserved - Copyright DrugLib.com, 2006-2017