磷酸乙酰化器状态影响Amifampridine (Firdapse)药物动力学和暴露在更大程度上比肾功能。
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Haroldsen PE、Sisic Z, Datt J,井DG, Ingenito G
磷酸乙酰化器状态影响Amifampridine (Firdapse)药物动力学和暴露在更大程度上比肾功能。
其他。2017年7月,39 (7):1360 - 1370。doi: 10.1016 / j.clinthera.2017.05.353。Epub 2017年6月19日。
- PubMed ID
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28641995 (在PubMed]
- 文摘
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目的:本研究的目的是评估安全性、耐受性和药代动力学(PK)属性的amifampridine磷酸(Firdapse)及其主要活性3-N-acetyl代谢物在肾功能受损和健康人慢乙酰化器(SA)和快速乙酰化器(RA)表型。方法:这是一个阶段的我,多中心、开放研究的PK属性和安全性amifampridine磷酸与正常个体,轻微、中度或严重肾功能受损。Amifampridine磷酸盐被作为一个10毫克(基础等效)剂量和血浆和尿液PK属性Amifampridine及其3-N-acetyl代谢物的测定。安全性评价是通过监测不良事件(AEs),临床实验室检测和物理考试。结果:Amifampridine间隙是主要通过N-acetylation代谢,不管肾功能的乙酰化器表型。在肾功能正常的患者,肾清除率代表大约3%和18%的总间隙amifampridine在RA和SA,分别。amifampridine暴露观察乙酰化表型之间的巨大差异在肾功能水平。意味着amifampridine AUC0-infinity曝光值和Cmax高出8.8倍在SA组与RA组肾功能水平。相比之下,意味着AUC0-infinity被乙酰化器组内肾功能的影响较小,只有2 - 3重更高的个人有严重肾功能损害(RI),而与正常的肾功能。接触amifampridine SA组与正常肾功能更高(AUC0-infinity,大约1.8倍; Cmax, approximately 4.1-fold) than the RA group with severe RI. Exposure to the inactive 3-N-acetyl metabolite was higher than amifampridine in both acetylator groups, independent of renal function level. The metabolite is cleared by renal excretion, and exposure was clearly dependent on renal function with 4.0- to 6.8-fold increases in AUC0-infinity from normal to severe RI. No new tolerability findings were observed. IMPLICATIONS: A single dose of 10 mg of amifampridine phosphate was well tolerated, independent of renal function and acetylator status. The results indicate that the PK profile of amifampridine is affected by metabolic acetylator phenotype to a greater extent than by renal function level, supporting Firdapse administration in individuals with RI in line with current labeling recommendations. Amifampridine should be dosed to effect per the individual patient need, altering administration frequency and dose in normal through severe RI. The therapeutic dose of amifampridine phosphate should be tailored to the individual patient needs by gradual dose titration up to the present maximum recommended dose (60-80 mg/day) or until dose-limiting AEs intervene to avoid overdosing and underdosing. EudraCT identifier: 2013-005349-35.
DrugBank数据引用了这篇文章
- 药物
- 药物酶
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药物 酶 类 生物 药理作用 行动 Amifampridine 芳基胺N-acetyltransferase 1 蛋白质 人类 没有底物细节 Amifampridine 芳基胺N-acetyltransferase 2 蛋白质 人类 没有底物细节 - 药物反应
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反应 细节
