A 2017 review outlines the issues with enzalutamide and various anticoagulants and suggests treatment options in patients requiring anticoagulation. The problem arises because enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a strong inducer of 3A4, which many anticoagulant medications are metabolized by. In vitro data also suggests that enzalutamide may inhibit P-glycoprotein (P-gp), which functions to expel toxins and xenobiotics from cells. Direct oral anticoagulants (DOACs) have some issues with enzalutamide. Apixaban and rivaroxaban both are heavily metabolized by CYP3A4, so concentrations would be theoretically lowered by coadministration with enzalutamide. Both drugs are also substrates of P-gp, which could theoretically increase the AUC and Cmax of these medications. Since enzalutamide has not been studied with either apixaban or rivaroxaban, the effect of coadministration is unknown. The manufacturers of both drugs recommend against their use with strong CYP3A4 inducers. Edoxaban shows a more favorable interaction profile with enzalutamide, as edoxaban is not significantly affected by CYP3A4 induction. However, P-gp inhibitors may still affect edoxaban levels. Still, no dose reductions are recommended for patients receiving edoxaban and enzalutamide simultaneously. Dabigatran does not undergo hepatic metabolism by CYP enzymes, but is affected by P-gp inhibitors. In patients taking dabigatran with a P-gp inhibitor, the manufacturer recommends a dosage reduction in patients who have moderate renal impairment (CrCl 30-50 mL/min) and discontinuation in patients with severe renal impairment (CrCl less than 30 mL/min). The authors recommend specific anticoagulation management strategies for patients on enzalutamide. [1]
Additionally, a 2017 article suggests caution when co-administering enzalutamide with either edoxaban or dabigatran in elderly, frail patients who have impaired renal functions. [2]
A 2024 Delphi consensus employed a rigorous three-stage modified electronic Delphi (e-Delphi) process to establish expert consensus on drug–drug interactions (DDIs) between androgen receptor axis-targeted therapies (ARATs) (abiraterone acetate, apalutamide, darolutamide, and enzalutamide) and commonly used oral antithrombotic therapies (ATTs), including direct oral anticoagulants (DOACs) such as apixaban, dabigatran, edoxaban, rivaroxaban, as well as warfarin and clopidogrel. A total of 163 relevant publications, product monographs, and established drug interaction databases were reviewed by the multidisciplinary team. The panel utilized detailed pharmacokinetic and pharmacodynamic evidence, supported by both in vitro and clinical data, to categorize the clinical significance of 24 ARAT/ATT drug pairs on a graded scale from negligible to catastrophic consequences, followed by consensus-based recommendations on management strategies. The e-Delphi process yielded consensus for 22 of 24 drug pairs regarding clinical interaction potential: five pairs were deemed to have negligible or minor risk, ten moderate, and seven major or catastrophic consequences. Notably, apalutamide and enzalutamide exhibited the highest potential for clinically relevant DDIs, particularly when co-administered with apixaban and rivaroxaban, driven by their strong induction of cytochrome P450 enzymes and modest induction of transporter proteins such as P-glycoprotein. The panel recommended avoiding 11 specific ARAT/ATT combinations and modifying dosing or monitoring for eight others, with only three pairs requiring no intervention. Darolutamide was identified as having the lowest DDI risk profile, making it preferable in patients requiring anticoagulation with dabigatran, edoxaban, or clopidogrel. These conclusions heavily relied on extrapolations from pharmacokinetic data and analogies to drugs with similar metabolic pathways, as direct clinical outcome data remain sparse. [3]
A 2023 research article detailed the development and verification of physiologically-based pharmacokinetic (PBPK) models for enzalutamide and its major active metabolite M2 to predict DDIs involving combined P-glycoprotein (P-gp) and CYP3A substrates, specifically apixaban and rivaroxaban. The work incorporated extensive in vitro assessments of CYP enzyme and P-gp induction and inhibition using freshly isolated human hepatocytes and MDR1-expressing cell lines. The PBPK simulations predicted that coadministration of 160 mg once-daily enzalutamide with apixaban would result in approximately a 31% reduction in apixaban area under the curve (AUC) without significant change in peak concentration (C_max), whereas rivaroxaban exposure was more substantially affected, with model outputs indicating a 42–45% decrease in AUC and roughly a 23–25% decrease in C_max depending on the inclusion of organic anion transporter 3 (OAT3) renal involvement. Sensitivity analyses exploring variations in intestinal P-gp activity demonstrated that alterations in P-gp had a minor influence on rivaroxaban exposure but a somewhat greater, yet still limited, effect on apixaban. The net effect of enzalutamide and M2 was characterized by combined CYP3A induction reducing systemic exposure of the anticoagulants, counterbalanced partially by weak P-gp inhibition. These modeling results aligned with clinical DDI findings involving digoxin, another P-gp substrate, and midazolam, a CYP3A probe, demonstrating the clinical plausibility of the models. Importantly, the PBPK approach highlighted the complexity of simultaneous induction and inhibition on transporters and enzymes by enzalutamide and provided quantitative estimates valuable for assessing the safety and efficacy risks when coadministering enzalutamide with direct oral anticoagulants in patients with prostate cancer. [4]
A 2022 review summarizes the pharmacokinetic and pharmacodynamic drug–drug interactions of DOACs. Enzalutamide, an androgen receptor antagonist, is a strong inducer of P-gp and CYP3A4 and a moderate inducer of CYP2C9/CYP2C19, so its use is contraindicated with all DOACs because it may substantially reduce DOAC exposure and anticoagulant efficacy; low-molecular-weight heparin is preferred for prostate cancer-associated VTE during enzalutamide. Overall, DOACs have fewer clinically relevant interactions than warfarin but still require careful evaluation, with possible dose reduction, avoidance, or staggered administration. [5]
Per a 2024 review, enzalutamide interactions with DOACs are driven mainly by CYP3A4 induction and, to a lesser extent, P-gp inhibition. Apixaban and rivaroxaban are dual CYP3A4/P-gp substrates; enzalutamide may have opposing effects, but CYP3A4 induction is expected to predominate and lower exposure. Physiologically based pharmacokinetic modeling predicts that enzalutamide 160 mg decreases apixaban AUC by about 31% with no change in Cmax, and decreases rivaroxaban AUC by about 45% and Cmax by about 25%, so coadministration should be carefully monitored with possible dose adjustment or therapy modification. Dabigatran and edoxaban are minimally metabolized by CYP enzymes and are mainly P-gp substrates; enzalutamide’s mild P-gp inhibition may increase their exposure, but this interaction is likely smaller than for apixaban and rivaroxaban. Still, monitor therapy closely, and for dabigatran in renal impairment, dose reduction or avoidance of coadministration may be needed. Overall, enzalutamide plus a DOAC requires pharmacist/cardiologist input, monitoring, and possible dose modification rather than being managed automatically. [6]