Direct oral anticoagulant use and drug–drug interactions in transplant recipients receiving calcineurin inhibitors

Abstract

Background

Direct oral anticoagulants (DOACs) are metabolized by CYP3A4 and/or transported by P-glycoprotein. Cyclosporine and tacrolimus can inhibit these pathways, potentially increasing DOAC exposure and bleeding risk. However, data on the relevance of these interactions in transplant recipients are limited.

Objectives

We aimed to study DOAC doses, plasma level monitoring, and interactions with calcineurin inhibitors in transplant recipients.

Methods

We retrospectively (2013-2024) included all adults treated at the University Hospitals Leuven, Belgium, who received both a DOAC and tacrolimus or cyclosporine and had at least 1 DOAC plasma level measurement. DOAC concentrations were compared with on-therapy ranges from phase 3 trials. Levels exceeding the 95th percentile of peak ranges (for peak and intermediate samples) or trough ranges (for trough samples) were classified as above range.

Results

Among 495 patients with coprescription, 216 patients had 360 DOAC measurements. The median age was 66 years (IQR, 59-72). Lung (31%) and kidney (29%) transplants were the most common. DOAC dosing was consistent with product labeling in 73% of measurements. Samples were obtained at peak (12%), trough (58%), or intermediate intervals (30%). Overall, 11% of measurements were above range: 4% for edoxaban, 18% for apixaban, and 20% for rivaroxaban. Above-range levels were associated with concomitant strong CYP3A4 or P-glycoprotein inhibitors, lower body weight, lower estimated glomerular filtration rate, cyclosporine use, and DOAC type.

Conclusion

In transplant recipients selected for DOAC plasma level monitoring, above-range DOAC concentrations were observed in a minority of patients but were more frequent among those with strong CYP3A4 or P-glycoprotein inhibitors, lower body weight, impaired kidney function, or cyclosporine use.