Figure 8. Molecular docking simulations of imatinib (A), sunitinib (B) and gefitinib (C) with CYP2J2, and (D, E and F) with CYP3A4.
Estimation of the DDI risk between rivaroxaban and the three TKIs
According to the inhibition constants of the TKIs for CYP2J2- and CYP3A4-mediated rivaroxaban metabolism, the AUC fold-changes when the TKIs were combined with rivaroxaban were predicted. All predictions were performed based on the Cmax of patients with solid tumours after administering recommended TKI doses (Gschwind et al., 2005; Scheffler, Di Gion, Doroshyenko, Wolf & Fuhr, 2011; Sparano et al., 2009). For patients with solid tumours, imatinib was predicted to influence rivaroxaban metabolism in vivo, leading to a 2.14–3.44-fold change in the AUC, which was predicted to result in a maximum rivaroxaban exposure increase of 244% (Table 6). Sunitinib and gefitinib were predicted to result in maximum rivaroxaban exposure increases of 2% and 11%, respectively.
Table 6. Prediction of drug interaction risk in vivo arising from inhibition of CYP2J2 and CYP3A4.