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Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways

BACKGROUND: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neuro...

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Autores principales: Huppertz, Andrea, Grond-Ginsbach, Caspar, Dumschat, Chris, Foerster, Kathrin I., Burhenne, Jürgen, Weiss, Johanna, Czock, David, Purrucker, Jan C., Rizos, Timolaos, Haefeli, Walter E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716843/
https://www.ncbi.nlm.nih.gov/pubmed/31464657
http://dx.doi.org/10.1186/s40360-019-0331-9
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author Huppertz, Andrea
Grond-Ginsbach, Caspar
Dumschat, Chris
Foerster, Kathrin I.
Burhenne, Jürgen
Weiss, Johanna
Czock, David
Purrucker, Jan C.
Rizos, Timolaos
Haefeli, Walter E.
author_facet Huppertz, Andrea
Grond-Ginsbach, Caspar
Dumschat, Chris
Foerster, Kathrin I.
Burhenne, Jürgen
Weiss, Johanna
Czock, David
Purrucker, Jan C.
Rizos, Timolaos
Haefeli, Walter E.
author_sort Huppertz, Andrea
collection PubMed
description BACKGROUND: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making. CASE PRESENTATION: We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91–321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41–230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249–463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5–1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways. CONCLUSIONS: This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.
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spelling pubmed-67168432019-09-04 Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways Huppertz, Andrea Grond-Ginsbach, Caspar Dumschat, Chris Foerster, Kathrin I. Burhenne, Jürgen Weiss, Johanna Czock, David Purrucker, Jan C. Rizos, Timolaos Haefeli, Walter E. BMC Pharmacol Toxicol Case Report BACKGROUND: Apixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making. CASE PRESENTATION: We describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91–321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41–230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249–463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5–1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways. CONCLUSIONS: This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure. BioMed Central 2019-08-29 /pmc/articles/PMC6716843/ /pubmed/31464657 http://dx.doi.org/10.1186/s40360-019-0331-9 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Case Report
Huppertz, Andrea
Grond-Ginsbach, Caspar
Dumschat, Chris
Foerster, Kathrin I.
Burhenne, Jürgen
Weiss, Johanna
Czock, David
Purrucker, Jan C.
Rizos, Timolaos
Haefeli, Walter E.
Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
title Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
title_full Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
title_fullStr Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
title_full_unstemmed Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
title_short Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
title_sort unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
topic Case Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716843/
https://www.ncbi.nlm.nih.gov/pubmed/31464657
http://dx.doi.org/10.1186/s40360-019-0331-9
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