Integration analysis of metabolites and single nucleotide polymorphisms improves the prediction of drug response of celecoxib.

Abstract

Pharmacogenetics and pharmacometabolomics are the common methods for personalized medicine, either genetic or metabolic biomarkers have limited predictive power for drug response. In order to better predict drug response, the study attempted to integrate genetic and metabolic biomarkers for drug pharmacokinetics prediction. The study chose celecoxib as study object, the pharmacokinetic behavior of celecoxib was assessed in 48 healthy volunteers based on UPLC-MS/MS platform, and celecoxib related single nucleotide polymorphisms (SNPs) were also detected. Three mathematic models were constructed for celecoxib pharmacokinetics prediction, the first one was mainly based on celecoxib-related SNPs; the second was based on the metabolites selected from a pharmacometabolomic analysis by using GC-MS/MS method, the last model was based on the combination of the celecoxib-related SNPs and metabolites above. The result proved that the last model showed an improved prediction power, the integration model could explain 71.0% AUC variation and predict 62.3% AUC variation. To facilitate clinical application, ten potential celecoxib-related biomarkers were further screened, which could explain 68.3% and predict 54.6% AUC variation, the predicted AUC was well correlated with the measured values (r=0.838). This study provides a new route for personalized medicine, the integration of genetic and metabolic biomarkers can predict drug response with a higher accuracy.