title: Effect of the Direct Oral Anticoagulants Rivaroxaban and Apixaban on the Disposition of Calcineurin Inhibitors in Transplant Recipients.
abstract: Calcineurin inhibitors (CNIs) and direct oral anticoagulants (DOACs) share certain metabolic pathways, but whether DOACs influence CNI exposure has not been assessed.
  
  
  
  A single-center retrospective analysis was performed including 39 organ recipients treated with the combination of a CNI and rivaroxaban (n = 29) or apixaban (n = 10). Dose-corrected CNI trough concentrations (C0/D) during 200 days before and after DOAC initiation were recorded (n = 261), together with covariates known to influence CNI disposition such as steroid dose and hematocrit. The average C0/D before and during DOAC therapy was compared using paired samples t test. Multivariable mixed models were constructed to estimate the effect of DOAC and other predictors on C0/D at each time point.
  
  
  
  Group average C0/D was not significantly different before and during DOAC therapy for any CNI-DOAC combination (P = 0.089-0.761), although C0/D changed >20% in 19/39 patients (13 increases, 6 decreases). In multivariable analysis, independent predictors of tacrolimus C0/D were methylprednisolone dose (P = 0.039) and concomitant use of a CYP3A inhibitor (P = 0.007). The subgroup analysis per DOAC showed a limited but significant effect of rivaroxaban on tacrolimus C0/D (9.2% increase, P = 0.042). Independent predictors of ciclosporin C0/D were age (P = 0.018) and use of any DOAC (12.1% increase, P = 0.020).
  
  
  
  Apixaban, and particularly rivaroxaban, may cause a limited (<20%) increase in CNI trough concentration, an effect that is unlikely to trigger a dose change. It may be prudent to perform an additional CNI trough concentration measurement 5-7 days after DOAC initiation, but preemptive CNI dose changes are not warranted based on these observations.
authors.affiliation: *Department of Microbiology and Immunology, KU Leuven-University of Leuven; Departments of †Nephrology and Renal Transplantation, ‡Pharmacy, §Pharmaceutical and Pharmacological Sciences, Clinical Pharmacology and Pharmacotherapy; ¶Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven-University of Leuven; Departments of ‖Hematology, **Cardiology, ††Respiratory diseases, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanhove
authors.forename: Isabel
authors.initials: I
authors.lastname: Spriet
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.forename: Johan
authors.initials: J
authors.lastname: Maertens
authors.forename: Johan
authors.initials: J
authors.lastname: Van Cleemput
authors.forename: Robin
authors.initials: R
authors.lastname: Vos
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuypers
mesh_terms: D000284:Administration, Oral; D000368:Aged; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D016377:Organ Transplantation / Q000379:methods*; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011728:Pyridones / Q000008:administration & dosage / Q000494:pharmacology*; D012189:Retrospective Studies; D000069552:Rivaroxaban / Q000008:administration & dosage / Q000494:pharmacology*; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D065095:Calcineurin Inhibitors; D065427:Factor Xa Inhibitors; D007166:Immunosuppressive Agents; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban; D000069552:Rivaroxaban; D016559:Tacrolimus