Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
Department of Neurology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
BMC Pharmacol Toxicol. 2019 Aug 29;20(1):53. doi: 10.1186/s40360-019-0331-9.
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.
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.
This case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.
阿哌沙班可有效降低非瓣膜性心房颤动患者发生缺血性卒中和全身性栓塞的风险。系统中阿哌沙班的暴露量取决于多种清除途径。尽管在神经急症情况下常规定量检测直接口服抗凝剂（DOAC）尚未广泛建立，但 DOAC 峰浓度与出血事件以及 DOAC 谷浓度与疗效和安全性的可疑关联表明，此类信息可能有助于临床决策。
我们描述了一位 75 岁女性心房颤动患者的病例，该患者服用阿哌沙班，因疑似急性脑卒中入院。临床检查未证实为缺血性或出血性脑卒中，但常规定量检测阿哌沙班发现其血药浓度过高（最后一次服药后约 3 小时：1100ng/ml（预期范围：91-321ng/ml）；服药后约 12 小时：900ng/ml（预期范围：41-230ng/ml））和消除半衰期显著延长（约 31 小时）。相应的阿哌沙班浓度与剂量比值分别为 9900（ng/ml）/（mg/kg/d）和 8100（ng/ml）/（mg/kg/d）（预期范围：249-463（ng/ml）/（mg/kg/d））。肾功能仅中度受损（肌酐 1.36mg/dl（0.5-1.1mg/dl），肌酐清除率 40ml/min）。基因分析显示，该患者为 CYP3A5*3/*3 非表达者，ABCG2 c.421C/A 杂合子，ABCB1 c.2677T/T 和 ABCB1 c.3435T/T 纯合子。在没有已知药物相互作用解释阿哌沙班清除受损的情况下，阿哌沙班浓度过高很可能是由中度肾功能损害与阿哌沙班清除途径的多种功能性多态性共同导致的。
本病例提示，共存的遗传多态性可能会损害多种阿哌沙班清除途径，从而显著增加其暴露量。
