J. Lee,1 S. Ji,1 S. Kim,2 K. Shin,3 S. Yi,1 K. Lim,1 S. Lee,1 J. Cho,1 K. Yu,1 I. Jang1; 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea, Republic of, 2Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon, Korea, Republic of, 3College of Pharmacy, Research Institute of Pharmaceutical Science, Kyungpook National University, Daegu, Korea, Republic of

BACKGROUND: Hepatotoxicity is a major challenge in drug development and use. Biomarkers are needed to predict the potential for drug-induced liver injury (DILI). In this study, we explored the potential utility of the serum microRNAs (miRNAs) as predictors of DILI in healthy subjects after multiple administration of Augmentin.
METHODS: An open-label, single-sequence study was conducted in 32 healthy male volunteers based on their GSTT1/M1 genotype with 8 subjects per group (GSTT1/M1; wild/wild, null/wild, wild/null, and null/null types). Subjects received oral doses of amoxicillin 750 mg/clavulanic acid 375 mg twice daily for 14 days. Blood samples were obtained for clinical laboratory test including liver function test, miRNA quantification and pharmacokinetic (PK) analysis before and after drug administration on day 1, 8, 14, 21 and 60. The correlation between potential biomarkers and liver function parameters were evaluated.
RESULTS: A total of 31 subjects completed the study and one subject dropped out due to headache and nausea. GSTT1/M1 genotypes were not associated with liver function test and PK parameters. Subjects were classified as a responder or non-responder based on fold change values of ALT (>2.0-fold: responder; n=9, <1.5-fold: non-responder; n=17). In responder group, liver-specific microRNA miR-122 levels significantly correlate with peak serum ALT change from baseline in day 21 and 60 after drug administration compared to baseline (Pearson’s correlation test, p <0.001).
CONCLUSION: GSTT1/M1 genotype was not associated with ALT elevation induced by amoxicillin/clavulanic acid. Serum miR-122 levels were highly correlated with ALT changes (Pearson’s r = 0.774). The potential of utility of miR-122 as an early biomarker of DILI needs to be further investigated.