Effects of Iguratimod on Warfarin, Diclofenac, and Celecoxib Metabolism, and Prediction of in vivo Drug—drug Interactions

Objective Iguratimod is an antirheumatic drug, launched in September 2012 in Japan. During post-marketing surveillance, severe side effects, such as bleeding and coagulopathies, were reported upon concomitant use with the anticoagulant agent, warfarin. To investigate whether this drug-drug interaction（DDI）occurred through inhibition of metabolism, the effects of iguratimod and its metabolite M2 （N-acetylated metabolite）, a major metabolite of iguratimod in human plasma on the metabolism of S-warfarin were examined. Furthermore, the in vivo DDIs between iguratimod and cytochrome P450 2C9（CYP2C9）substrates were predicted from the in vitro data. Methods The in vitro inhibitory effects of iguratimod and M2 on the metabolism of S-warfarin were examined using human liver microsomes. In addition, CYP2C9 substrates diclofenac and celecoxib were also used as references in the study. Based on the data from this study and other literatures, the increases in area under the concentration-time curve（AUC）of S-warfarin, diclofenac, and celecoxib when used concomitantly with iguratimod were estimated using static or dynamic model approaches. Results Iguratimod and M2 inhibited the metabolism of S-warfarin, with IC50 values of 14.7 and 21.0μmol╱L, respectively. Iguratimod and M2 also inhibited CYP2C9 substrate metabolism, with IC50 values of 11.7 and 22.1μmol╱L for diclofenac, and 8.22 and 17.7μmol╱L for celecoxib, respectively. The AUC increase of celecoxib when used concomitantly with iguratimod was estimated to be 1.16 using a dynamic model, although those of S-warfarin, diclofenac, and celecoxib were estimated to be 1.22-, 1.16- and 1.34-fold, respectively, using static model approach. Conclusion The results in this study suggest that iguratimod would not affect the exposure of these concomitant drugs, although iguratimod and M2 do inhibit CYP2C9-catalyzed metabolism.