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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) 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.

SUBMITTER: Huppertz A

PROVIDER: S-EPMC6716843 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Huppertz Andrea A Grond-Ginsbach Caspar C Dumschat Chris C Foerster Kathrin I KI Burhenne Jürgen J Weiss Johanna J Czock David D Purrucker Jan C JC Rizos Timolaos T Haefeli Walter E WE

BMC pharmacology & toxicology 20190829 1

<h4>Background</h4>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 sug ...[more]

PMID: 31464657

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

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

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