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 (Ki,u) values of 12.43 ± 0.28 and 3.89 ± 0.40 μM, respectively. Based on the in vitro Ki,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 Ki,u ([I]gut/Ki,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.