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.

中文翻译：

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意外的过量apixaban暴露：具有多个apixaban消除途径多态性的患者的病例报告。

背景技术阿哌沙班可有效降低非瓣膜性房颤患者的缺血性中风和全身性栓塞的风险。给定阿哌沙班剂量的全身暴露取决于多种清除途径。尽管尚未广泛建立神经系统紧急情况下直接口服抗凝剂（DOAC）的常规定量方法，但怀疑DOAC峰值浓度与出血事件以及DOAC谷浓度与功效和安全性之间的关联性表明，此类信息可能支持临床决策。病例介绍我们描述了一名75岁的妇女在apixaban上发生房颤的案例，该妇女因怀疑是急性中风而入院。临床检查并未证实缺血性或出血性中风，但常规定量的阿哌沙班显示血浆阿哌沙班的血浆浓度过高（最后一次服药后约3小时：1100 ng / ml（预期范围：91-321 ng / ml）；〜药物摄入后12小时：900 ng / ml（预期范围：41-230 ng / ml），消除半衰期大大延长（〜31 h）。相应的阿哌沙班浓度/剂量比分别为9900（ng / ml）/（mg / kg / d）和8100（ng / ml）/（mg / kg / d）（预期范围：249-463（ng / ml）/（mg / kg / d））。肾功能仅受到中度损害（肌酐1.36 mg / dl（0.5-1.1 mg / dl），肌酐清除率40 ml / min）。基因型分析显示该患者为CYP3A5 * 3 / * 3非表达子，ABCG2 c.421C / A等位基因的杂合子，ABCB1 c.2677 T / T和ABCB1 c.3435 T / T的纯合子T. 在没有已知药物相互作用解释阿哌沙班清除障碍的情况下，阿哌沙班浓度过高最有可能是由于中度肾功能不全和阿哌沙班清除途径的多种功能性多态性引起的。结论该病例表明，同时存在的遗传多态性可损害多种阿哌沙班消除途径，从而显着增加其暴露程度。