Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways
Abstract 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)...
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doaj-f2397f03fe9e43688aa9e654a92631652020-11-25T03:43:32ZengBMCBMC Pharmacology and Toxicology2050-65112019-08-012011610.1186/s40360-019-0331-9Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathwaysAndrea Huppertz0Caspar Grond-Ginsbach1Chris Dumschat2Kathrin I. Foerster3Jürgen Burhenne4Johanna Weiss5David Czock6Jan C. Purrucker7Timolaos Rizos8Walter E. Haefeli9Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University HospitalDepartment of Neurology, Heidelberg University HospitalDepartment of Neurology, Heidelberg University HospitalDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University HospitalDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University HospitalDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University HospitalDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University HospitalDepartment of Neurology, Heidelberg University HospitalDepartment of Neurology, Heidelberg University HospitalDepartment of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University HospitalAbstract 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.http://link.springer.com/article/10.1186/s40360-019-0331-9Direct oral anticoagulantsApixabanPlasma concentrationNeurology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrea Huppertz Caspar Grond-Ginsbach Chris Dumschat Kathrin I. Foerster Jürgen Burhenne Johanna Weiss David Czock Jan C. Purrucker Timolaos Rizos Walter E. Haefeli |
spellingShingle |
Andrea Huppertz Caspar Grond-Ginsbach Chris Dumschat Kathrin I. Foerster Jürgen Burhenne Johanna Weiss David Czock Jan C. Purrucker Timolaos Rizos Walter E. Haefeli Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways BMC Pharmacology and Toxicology Direct oral anticoagulants Apixaban Plasma concentration Neurology |
author_facet |
Andrea Huppertz Caspar Grond-Ginsbach Chris Dumschat Kathrin I. Foerster Jürgen Burhenne Johanna Weiss David Czock Jan C. Purrucker Timolaos Rizos Walter E. Haefeli |
author_sort |
Andrea Huppertz |
title |
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_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_sort |
unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways |
publisher |
BMC |
series |
BMC Pharmacology and Toxicology |
issn |
2050-6511 |
publishDate |
2019-08-01 |
description |
Abstract 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. |
topic |
Direct oral anticoagulants Apixaban Plasma concentration Neurology |
url |
http://link.springer.com/article/10.1186/s40360-019-0331-9 |
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