In vitro assessment of inhibitory effects of kinase inhibitors on CYP2C9, 3A and 1A2: Prediction of drug-drug interaction risk with warfarin and direct oral anticoagulants

Abstract

Objective: This study aimed to evaluate the cytochrome P450 (CYP)-mediated drug-drug interaction (DDI) potential of kinase inhibitors with warfarin and direct oral anticoagulants (DOACs).

Methods: An in vitro CYP probe substrate cocktail assay was used to study the inhibitory effects of fifteen kinase inhibitors on CYP2C9, 3A, and 1A2. Then, DDI predictions were performed using both mechanistic static and physiologically-based pharmacokinetic (PBPK) models.

Results: Linsitinib, masitinib, regorafenib, tozasertib, trametinib, and vatalanib were identified as competitive CYP2C9 inhibitors (K_i = 1.4, 1.0, 1.1, 3.8, 0.5, and 0.1 μM, respectively). Masitinib and vatalanib were competitive CYP3A inhibitors (K_i = 1.3 and 0.2 μM), and vatalanib noncompetitively inhibited CYP1A2 (K_i = 2.0 μM). Moreover, linsitinib and tozasertib were CYP3A time-dependent inhibitors (K_I = 26.5 and 400.3 μM, k_inact = 0.060 and 0.026 min^-1, respectively). Only linsitinib showed time-dependent inhibition of CYP1A2 (K_I = 13.9 μM, k_inact = 0.018 min^-1). Mechanistic static models identified possible DDI risks for linsitinib and vatalanib with (S)-/(R)-warfarin, and for masitinib with (S)-warfarin. PBPK simulations further confirmed that vatalanib may increase (S)- and (R)-warfarin exposure by 4.37- and 1.80-fold, respectively, and that linsitinib may increase (R)-warfarin exposure by 3.10-fold. Mechanistic static models predicted a smaller risk of DDIs between kinase inhibitors and apixaban or rivaroxaban. The greatest AUC increases (1.50-1.74) were predicted for erlotinib in combination with apixaban and rivaroxaban. Linsitinib, masitinib, and vatalanib were predicted to have a smaller effect on apixaban and rivaroxaban AUCs (AUCR 1.22-1.53). No kinase inhibitor was predicted to increase edoxaban exposure.

Conclusions: Our results suggest that several kinase inhibitors, including vatalanib and linsitinib, can cause CYP-mediated drug-drug interactions with warfarin and, to a lesser extent, with apixaban and rivaroxaban. The work provides mechanistic insights into the risk of DDIs between kinase inhibitors and anticoagulants, which can be used to avoid preventable DDIs in the clinic.

Keywords: CYP time-dependent inhibition; CYP-mediated drug-drug interaction; Direct oral anticoagulants; Kinase inhibitors; Mechanistic static and physiologically-based pharmacokinetic models; Warfarin.