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.

Risk assessment and molecular mechanism study of drug-drug interactions between rivaroxaban and tyrosine kinase inhibitors mediated by CYP2J2/3A4 and BCRP/P-gp

“…Therefore, we speculated that sunitinib decreased exposure by promoting BCRP efflux transportation and then increasing rivaroxaban excretion. Lafaie et al also evaluated the DDI risks in combinations of DOACs with TKIs using in vitro cell models ( Lafaie et al, 2022 ). Imatinib was also predicted to have intestinal DDI risks based on P-gp when combined with rivaroxaban.…”

Management of Cancer-Associated Thrombosis in France: A National Survey among Vascular Disease and Supportive Care Specialists

“…Even if no clinical relevance has been demonstrated yet, they are worried about the possible interaction (mostly for drugs with both CYP 3A4 and pGP metabolism), while an alternative (LMWH) at least as effective is available but requires injections. This issue is very complex, since not only the pharmacodynamic interaction but also the characteristics of patients (absorption, renal and hepatic impairment…) could interfere with the level of interaction and the clinical impact [ 13 , 14 , 16 ]. Studies with different patient profiles and clinical outcomes are definitely required on this matter.…”

“…In particular, the risk of gastrointestinal (GI) bleeding is a concern with DOACs, specifically for patients with gastrointestinal cancer [ 6 , 12 ]. Additionally, there is increasing questioning of the potential consequences related to the concomitant prescription of DOACs and some anticancer treatments and, more importantly, their clinical relevance [ 13 , 14 , 15 , 16 ]). The occurrence of complications, such as VTE recurrence or thrombocytopenia, frequently complicates the management of patients with CAT, with few available data in the literature to help clinicians facing those situations [ 17 ].…”

Drug–drug interactions of protein kinase inhibitors in chronic myeloid leukaemia patients: A study using the French health insurance database

“…These patients all received dasatinib as second treatment, and the median time between the switch of PKI and the death for these patients was 3 months (range 2-3). Most patients (n = 3409, 98% of the cohort) were using another drug along with a PKI; the median number of concomitant medications was 2 (1-3) at the beginning of PKI treatment and 14 (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21) over the first year of follow-up. Paracetamol (61%) and proton pump inhibitors (PPIs) (46%) were the most frequently used drugs during the first year of follow-up.…”

“…For this reason, another drug used concomitantly with a PKI is likely to affect PKI metabolisation via the CYP3A4 isozyme [17]. Use of PKIs with other drugs that decrease absorption or induce metabolisation of PKI may result in subtherapeutic levels and bring about a decrease in PKI effect [18][19][20][21]. On the other hand, drugs that inhibit the PKI metabolism may also cause supratherapeutic drug levels and toxicity [22][23][24][25].…”