Drug–Drug Interactions of 257 Antineoplastic and Supportive Care Agents With 7 Anticoagulants: A Comprehensive Review of Interactions and Mechanisms

Abstract

Data on drug–drug interactions (DDI) of antineoplastic drugs with anticoagulants is scarce. We aim to evaluate factors associated with DDI of antineoplastic and supportive care drugs with anticoagulants resulting in modification of pharmacokinetics of these last mentioned. A literature review on DDI databases and summaries of products characteristics (SmPC) was done. Drug–drug interactions of 257 antineoplastic and supportive care drugs with direct oral anticoagulants (DOACs), warfarin, enoxaparin, or fondaparinux were categorized as no clinically significant expected DDI, potentially weak DDI, potentially clinically significant DDI, and recommendation against coadministration. Logistic regression models were performed to analyze the association between the dependent variable potentially clinically significant interaction/recommendation against coadministration and the mechanisms of DDI. Of the 1799 associations, 84.4% were absence of DDI, 3.6% potentially weak DDI, 10.2% potentially clinically relevant DDI, and 2.0% recommendation against coadministration. Warfarin has higher DDI potential than other anticoagulants. Enoxaparin and fondaparinux have fewer DDI than others. There was no difference between DOACs. Drug–drug interactions with apixaban and rivaroxaban was independently associated with the absence of CYP3A4 competition, P-glycoprotein inhibition, CYP3A4 induction, and drug class of tyrosine kinase inhibitors. Drug–drug interactions with dabigatran and edoxaban was associated with inhibition of P-glycoprotein and tyrosine kinase inhibitors. Warfarin, induction of CYP3A4, and inhibition of CYP2C9. Enoxaparin and fondaparinux, only tyrosine kinase inhibitors. Direct oral anticoagulants did not differ regarding DDI with antineoplastic agents. Warfarin presented more DDI than other anticoagulants. P-glycoprotein inhibition and CYP3A4 induction were independently associated with DDI of antineoplastic agents with DOACs.

Treatment Algorithm in Cancer-Associated Thrombosis: Updated Canadian Expert Consensus

“…All DOACs are substrates of P-glycoprotein, and apixaban and rivaroxaban are also substrates of CYP3A4, so therapies that affect P-glycoprotein or CYP3A4 metabolism have the potential to interact with DOACs [ 56 ]. Numerous anticancer therapies are inhibitors or inducers of the P-glycoprotein and/or CYP3A4 pathways, with the potential to interact with DOACs [ 57 ]. Anticancer therapies for which the potential for drug–drug interactions with DOACs should be considered include abiraterone, acalabrutinib, afatinib, ceritinib, cyclosporine, cobimetinib, crizotinib, dabrafenib, dasatinib, dexamethasone, doxorubicin, enzalutamide, erdafitinib, ibrutinib, idelalisib, imatinib, ipilimumab, lapatinib, mitotane, neratinib, nilotinib, nintedanib, niraparib, olaparib, panobinostat, ponatinib, ribociclib, sunitinib, tacrolimus, tamoxifen, trametinib, trastuzumab emtansine, vandetanib, vemurafenib, and vinblastine [ 57 ].…”

Cancer‐associated thrombosis and drug–drug interactions of antithrombotic and antineoplastic agents

“…Because warfarin interacts with many drugs, it is important to control DDIs when treatment is changed, and its interaction with frequently used anticancer drugs is given in Table 1. As demonstrated by a comprehensive review, warfarin has a higher DDI than enoxaparin with antineoplastic and supportive care agents (potentially clinically relevant DDI rate 23% vs. 8.2% and avoidance of coadministration rate 2.7% vs. 0, respectively) 21 . This was because the metabolism of warfarin interacts with multiple CYP enzymes (2C9, major), whereas the metabolism of enoxaparin was not related to the CYP enzyme system (Table 2).…”

Prévention et prise en charge des thromboses associées au cancer: questions pratiques à propos de l’anticoagulation

“…Selon que ces agents sont inhibiteurs ou inducteurs du CYP3A4, ils sont susceptibles d'induire un risque hémorragique ou thrombotique résultant de l'activité modifiée de l'anticoagulant oral direct donné simultanément. Une étude pharmacologique évaluant environ 250 antitumoraux suggère un risque d'interaction cliniquement pertinente très augmenté en cas d'administration d'un anticoagulant oral direct chez des patients traités par ITK (OR après ajustement : 6,60, IC95 % 2,08-20,95 avec l'apixaban par exemple) [56]. Le risque d'interactions médicamenteuses est donc un paramètre majeur à prendre en compte dans le choix du traitement anticoagulant des CAT établies, comme souligné dans les avis d'experts ou les recommandations des diverses sociétés savantes [12][13][14]48] et dans les référentiels de l'AFSOS [18].…”