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Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care

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Abstract

Factor Xa-inhibitor apixaban is an oral anticoagulant prescribed in atrial fibrillation (AF) for stroke prevention. Its pharmacokinetic profile is known to be affected by cytochrome P450 (CYP)3A metabolism, while it is also a substrate of the efflux transporters ATP-binding cassette (ABC)B1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein, BCRP). In this study, we assessed the impact of interacting medication and pharmacogenetic variation to better explain apixaban concentration differences among 358 Caucasian AF patients. Genotyping (ABCG2, ABCB1, CYP3A4*22, CYP3A5*3) was performed by TaqMan assays, and apixaban quantified by mass spectrometry. The typical patient was on average 77.2 years old, 85.5 kg, and had a serum creatinine of 103.1 µmol/L. Concomitant amiodarone, an antiarrhythmic agent and moderate CYP3A/ABCB1 inhibitor, the impaired-function variant ABCG2 c.421C > A, and sex predicted higher apixaban concentrations when controlling for age, weight and serum creatinine (multivariate regression; R2 = 0.34). Our findings suggest that amiodarone and ABCG2 genotype contribute to interpatient apixaban variability beyond known clinical factors.

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Acknowledgements

We would like to thank Racquel Jandoc for help with clinical data entry. This work was supported by the Wolfe Medical Research Chair in Pharmacogenomics, the Ontario Ministry of Research, Innovation and Science (Ontario Research Fund—Research Excellence [RE08-063], Principal Investigator: Kim RB), and the Canadian Institutes of Health Research: Drug Safety and Effectiveness Network [DSEN-PREVENT, FRN-117588], Principal Investigator: Kim RB; Personalized Health Catalyst Grant [PCG-154864], Principal Investigator: Schwarz UI.

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada

    Markus Gulilat, Denise Keller, Bradley Linton, George K. Dresser, Jeffrey Alfonsi, Rommel G. Tirona, Richard B. Kim & Ute I. Schwarz

  2. Department of Physiology and Pharmacology, Western University, London, ON, Canada

    George K. Dresser, Rommel G. Tirona, Richard B. Kim & Ute I. Schwarz

  3. Department of Epidemiology and Biostatistics, Western University, London, ON, Canada

    A. Demetri Pananos & Daniel Lizotte

  4. London Health Sciences Centre, University Hospital, Western University, 339 Windermere Road, London, ON, N6A 5A5, Canada

    Ute I. Schwarz

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Gulilat, M., Keller, D., Linton, B. et al. Drug interactions and pharmacogenetic factors contribute to variation in apixaban concentration in atrial fibrillation patients in routine care. J Thromb Thrombolysis 49, 294–303 (2020). https://doi.org/10.1007/s11239-019-01962-2

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