Dose adjustment of celecoxib based on CYP2C9 genotype in healthy Koreans

Purpose: Celecoxib is a selective cyclooxygenase 2 (COX-2) inhibitor and is used for the treatment of rheumatoid arthritis and osteoarthritis. Celecoxib is extensively metabolized by hydroxylation, mediated by CYP2C9 and further oxidation. It is reported that CYP2C9 genetic polymorphism can affects the pharmacokinetic and pharmacodynamic changes of several NSAIDs, including celecoxib. We studied the optimal dose adjustment of celecoxib in relation to CYP2C9 genotype in healthy Koreans.

Methods: After the preliminary study with 26 subjects with different CYP2C9 genotypes, verification study was performed with 31 healthy Koreans. They were divided into two groups according to CYP2C9 genotype, CYP2C9EM (CYP2C9*1/*1, n=17) and CYP2C9IM (CYP2C19*1/*3, n=14). After overnight fasting, each study group received a single oral dose of 200 mg and 125 mg celecoxib, respectively. Blood samples were collected up to 48 hr after drug intake, and plasma concentrations of celecoxib were determined by using LC-MS/MS system.

Results: In the verification study, oral clearance (CL/F) of celecoxib in CYP2C9IM group was significantly lower compared to that in CYP2C9EM group (96.7 ± 31.2 L/hr vs. 53.6 ± 14.8 L/hr, P<0.0001), but other pharmacokinetic parameters of celecoxib between two groups were not significantly different. AUC_inf of celecoxib in CYP2C9EM and CYP2C9IM group was 2226.3 ± 573.8 ng·hr/mL and 2502.3 ± 679.2 ng·hr/mL, respectively.

Conclusion: Doses of celecoxib used in this study can be helpful to optimize the CYP2C9 genotype-based doses of celecoxib.