Pharmacokinetics of apixaban and tacrolimus or cyclosporine in kidney and lung transplant recipients

Holly Mansell, Ahmed Shoker, Jane Alcorn, Mark E Fenton, Julian S Tam, William Semchuk, Babar Bashir, Walter K Kraft, Shenzhen Yao, James D Douketis, Holly Mansell, Ahmed Shoker, Jane Alcorn, Mark E Fenton, Julian S Tam, William Semchuk, Babar Bashir, Walter K Kraft, Shenzhen Yao, James D Douketis

Abstract

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 (AUC0-inf ) geometric least square means (90% confidence interval [CI]) of 4312 (95% CI 3682, 5049) and 5388 (95% CI 3277, 8858), respectively. Compared to healthy subjects, the associated geometric mean ratios (GMRs) for apixaban maximum plasma concentration (Cmax ), AUC from time zero to the last quantifiable concentration (AUC0-tlast ) and AUC0-inf were 197% (95% CI 153, 295), 244% (95% CI 184, 323), and 224% (95% CI 170, 295) for transplant recipients on tacrolimus. The GMR (90% CI) Cmax , AUC0-tlast , and AUC0-inf of apixaban for patients on cyclosporine were 256% (95% CI 184, 358), 287% (95% CI 198, 415), and 280% (95% CI 195, 401). Kidney and lung transplant recipients receiving tacrolimus had higher apixaban exposure. A similar trend was noted for patients receiving cyclosporine, but additional patients are needed to confirm this interaction. Future studies are needed before apixaban can be safely recommended in this population, and the impact of dose staggering should be investigated. This study highlights the importance of pharmacokinetic studies in actual patient populations.

Trial registration: ClinicalTrials.gov NCT04023760.

Conflict of interest statement

The authors declared no competing interests for this work.

© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

FIGURE 1
FIGURE 1
Safety assessments
FIGURE 2
FIGURE 2
Plasma apixaban concentration–time profiles in transplant recipients (n = 9) stabilized on tacrolimus following a single oral dose of apixaban (10 mg)
FIGURE 3
FIGURE 3
Plasma apixaban concentration–time profiles in transplant recipients (n = 4) stabilized on cyclosporine following a single oral dose of apixaban (10 mg)

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