tacrolimus and apixaban

Apixaban is frequently used off-label in transplant recipients. However, a potential drug interaction exists with the calcineurin inhibitors. We conducted an open-label drug-drug interaction study to determine the pharmacokinetics of apixaban in lung and kidney transplant recipients who were taking a calcineurin inhibitor. A single dose of apixaban 10 mg was administered orally to kidney and lung transplant recipients maintained on either tacrolimus or cyclosporine, and pharmacokinetic parameters were compared to a reference cohort of 12 healthy subjects who used the same apixaban dose and pharmacokinetic blood sampling. Fourteen participants were enrolled (n = 6 kidney, n = 8 lung), with 10 maintained on tacrolimus and four on cyclosporine. Data from 13 participants was usable. Participants were taking triple therapy immunosuppression and had a mean (SD) of 12 (3) medications. Participants receiving tacrolimus and cyclosporine had area under the plasma concentration-time curve from time zero to infinity (AUC

Topics: Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Humans; Immunosuppressive Agents; Kidney; Lung; Pyrazoles; Pyridones; Tacrolimus; Transplant Recipients

Apixaban is metabolized by cytochrome P450 (CYP) 3A4 in the liver and intestine, undergoes direct intestinal excretion, and is a substrate to permeability glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. We examined the drug interactions between cyclosporine and tacrolimus (combined inhibitors of CYP3A4, P-gp, and BCRP) with apixaban in 12 healthy adult male volunteers. Apixaban 10 mg was administered orally alone, in combination with 100 mg cyclosporine or 5 mg tacrolimus. Co-administration with cyclosporine resulted in increase in apixaban maximum plasma concentration (C

Topics: Adult; Anticoagulants; Area Under Curve; Atrial Fibrillation; Calcineurin Inhibitors; Cross-Over Studies; Cyclosporine; Drug Interactions; Graft Rejection; Healthy Volunteers; Humans; Male; Middle Aged; Organ Transplantation; Pyrazoles; Pyridones; Tacrolimus; Venous Thromboembolism; Young Adult

The solid organ transplant community is slow to adopt the routine practice of using direct oral anticoagulants. Rivaroxaban and apixaban share common metabolic pathways with tacrolimus. This study aimed to clarify the impact of rivaroxaban/apixaban on tacrolimus troughs. Fifty solid organ transplant recipients with concomitant use of tacrolimus and rivaroxaban/apixaban were retrospectively assessed for changes in tacrolimus troughs and dose. Average dose-adjusted tacrolimus troughs and average tacrolimus total daily doses prior to and after rivaroxaban/apixaban initiation were compared. Subgroup analyses evaluating rivaroxaban and apixaban individually were performed. Rivaroxaban was prescribed to 18 recipients, and apixaban was prescribed to 32 recipients. Transplanted organs included kidney (n = 22), lung (n = 18), liver (n = 7), simultaneous pancreas and kidney (n = 1), and simultaneous kidney and liver (n = 2). The median doseadjusted tacrolimus trough and tacrolimus total daily dose prior to rivaroxaban/apixaban initiation was 2.15 ng/mL/mg (IQR 1.17, 3.37) and 4 mg (IQR 1.88, 6.25), respectively. The median dose-adjusted tacrolimus trough and tacrolimus total daily dose after rivaroxaban/apixaban initiation was 2.16 ng/mL/mg (IQR 1.24, 4.10) and 3.55 mg (IQR 1.5, 6.35), respectively. No significant difference was found between average dose-adjusted tacrolimus troughs or tacrolimus total daily doses before and after rivaroxaban/apixaban initiation or in the individual subgroup analyses for rivaroxaban/apixaban. It is unlikely that initiating rivaroxaban/apixaban affects tacrolimus troughs or requires tacrolimus dose adjustment. This study does not elucidate if tacrolimus affects rivaroxaban/apixaban pharmacokinetics or pharmacodynamics.

Topics: Humans; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Tacrolimus

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.

Topics: Administration, Oral; Aged; Calcineurin Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Factor Xa Inhibitors; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Multivariate Analysis; Organ Transplantation; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Tacrolimus