Drug–Drug Interactions Between Oral Anticoagulants and Calcineurin Inhibitors in Nephrotic Syndrome for Management of Thromboembolism

Thromboembolism is a life-threatening complication of nephrotic syndrome, which is treated with oral anticoagulants (warfarin and direct oral anticoagulants [DOACs]) that possess a variety of pharmacokinetic characteristics. This narrative review focused on drug–drug interactions between oral anticoagulants and calcineurin inhibitors (CNIs) (e.g., tacrolimus, cyclosporine, and voclosporin) for the management of thromboembolism in nephrotic syndrome. While warfarin has less potential for interacting with CNIs, DOACs carry a risk of drug–drug interactions with CNIs owing to the inhibition of drug-metabolizing enzymes and transporters, including cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. Specifically, a significant increase in DOAC exposure was observed when DOACs were co-administered with cyclosporine, a more potent P-glycoprotein inhibitor than tacrolimus. Limited evidence suggests that more pronounced drug interactions occur in specific cases: (1) apixaban and CNIs in patients with renal impairment, (2) edoxaban combined with cyclosporine in patients with renal impairment, and (3) a combination of rivaroxaban with dual inhibitors of P-glycoprotein and CYP3A4 (e.g., cyclosporine and fluconazole). From a pharmacological viewpoint, CNI-induced nephrotoxicity and hypertension may increase the risk of critical bleeding in patients receiving DOACs. In addition, the variation factors of pharmacokinetic parameters, such as renal function, pharmacogenomic profiles, and pathophysiological changes directly caused by nephrotic syndrome, may vary between patients, which could potentially augment the magnitude of drug–drug interactions between oral anticoagulants and CNIs. Further studies are required to understand the clinical significance of drug interactions in patients with nephrotic syndrome.