Tyrosine kinase inhibitors and direct oral anticoagulants: In vitro evaluation of drug-drug interaction mediated by P-glycoprotein

Abstract

Direct oral anticoagulants (DOACs) are now an option in the prevention and treatment of venous thromboembolic events (VTE) in patients with active cancer. Pharmacokinetics of DOACs are largely influenced by efflux transporters derived from ABC transporters, notably by P-glycoprotein (P-gp). The aim of this study was to assess the potential P-gp-mediated drug-drug interactions between 11 tyrosine kinase inhibitors (TKIs) with apixaban and rivaroxaban. Bidirectional permeabilities of apixaban and rivaroxaban were investigated across MDCK-MDR1 models, to determine half maximal inhibitory concentration (IC₅₀ ). Several categories of interaction risks based on IC₅₀ values can be distinguished depending on the TKI and DOAC used. IC₅₀ values of less than 10 μM were observed with the combination of erlotinib, nilotinib with both DOACs, and with dabrafenib and apixaban. IC₅₀ values between 10 and 100 μM were seen for axitinib, crizotinib, dasatinib, imatinib, and lapatinib with apixaban, and for axitinib, crizotinib, dabrafenib, idelalisib, imatinib, and vemurafenib with rivaroxaban. A risk of drug-drug interaction was found in vitro between TKIs and DOACs. In vivo pharmacokinetic studies are needed to ensure the safety of prescribing DOACs in cancer patients on TKI therapy, in order to avoid major, potentially preventable bleeding events.

Keywords: P-glycoprotein; direct oral anticoagulant; drug-drug interaction; in vitro model; tyrosine kinase inhibitor.