Pharmacogenomic variations associated with drug response of rifampin in Korean patients

초록

Background and Aims Rifampin (RIF) shows a wide inter-individual variation of its pharmacokinetics leading to treatment failure. Limited clinical evidence was reported on pharmacogenomic variants in association with the disposition of RIF, most of which were done on Caucasian or African subjects. In this study, we aim to discover and evaluate drug absorption, distribution, metabolism, and excretion(ADME) genetic biomarkers associated with the pharmaco-kinetics (PK) of RIF in Korean patients. Methods The interindividual variability of clearance (ηCL/F) value of RIF was estimated using an in-house population pharmacokinetics model. We selected the lower end of the distribution of ηCL/F (below 0.25, corresponding to percentile 25) as“cases”, and above percentile 75 as“controls”. Genotyping was performed by an Infinium Global Diversity Array with Enhanced PGx array. The genotyping results were validated by comparison with SNaPshot genotyping data for targeted biomarkers in pharmacogenes. Results After quality control, a total of 727,658 SNPs were detected from 317 subjects. Compared with previous studies on the distribution of ADME markers in the Korean population,our study showed the consistent result. An rs17137390 SNP located in the intergenic region of SLCO4C1 and ST8SIA4 genes showed the trend to be associated with PK of RIF under the dominant genetic model (OR: 7.3, 95% CI: 2.19-25,p=4.5*10-5). Our genotyping data is ongoingly generated and will serve as core data for genetic association results. Conclusion The genetic biomarkers of ADME genes could be useful to predict the potential cause of pharmacokinetics variability of RIF in Korean patients. Acknowledgment This work was supported by the National Research Foundation of Korea (NRF) grant (No.2018R1A5A2021242) funded by the Korean government (MSIT).