Prediction of Drug–Drug Interaction Between Dabrafenib and Irinotecan via UGT1A1-Mediated Glucuronidation

Background Dabrafenib and irinotecan are two drugs that can be utilized to treat melanoma. A previous in vivo study has shown that dabrafenib enhances the antitumor activity of irinotecan in a xenograft model with unclear mechanism. Objectives This study aims to investigate the inhibition of dabrafenib on SN-38 (the active metabolite of irinotecan) glucuronidation, trying to elucidate the possible mechanism underlying the synergistic effect and to provide a basis for further development and optimization of this combination in clinical research. Methods Recombinant human uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and human liver microsomes (HLMs) were employed to catalyze the glucuronidation of SN-38 in vitro. Inhibition kinetic analysis and quantitative prediction study were combined to predict drug–drug interaction (DDI) potential in vivo. Results Dabrafenib noncompetitively inhibited SN-38 glucuronidation in pooled HLMs and recombinant UGT1A1 with unbound inhibitor constant ( K i,u ) values of 12.43 ± 0.28 and 3.89 ± 0.40 μM, respectively. Based on the in vitro K i,u value and estimation of kinetic parameters, dabrafenib administered at 150 mg twice daily may result in about a 1−2% increase in the area under the curve (AUC) of SN-38 in vivo. However, the ratios of intra-enterocyte concentration of dabrafenib to K i,u ([ I ] gut / K i,u ) are 2.73 and 8.72 in HLMs and recombinant UGT1A1, respectively, indicating a high risk of intestinal DDI when dabrafenib was used in combination with irinotecan. Conclusion Dabrafenib is a potent noncompetitive inhibitor of UGT1A1 and may bring potential risk of DDI when combined with irinotecan.