食物摄入量对磷酸Amifampridine盐健康成年人的相对生物利用度。

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Haroldsen PE、井DG,汉森B,林班,奥尼尔CA

食物摄入量对磷酸Amifampridine盐健康成年人的相对生物利用度。

其他。2015年7月1;37 (7):1555 - 63。doi: 10.1016 / j.clinthera.2015.05.498。Epub 2015 6月20。

PubMed ID
26101174 (在PubMed
]
文摘

4-diaminopyridine目的:Amifampridine(3)在欧盟已经批准用于治疗Lambert-Eaton肌无力的综合症。Amifampridine狭窄的治疗指数,supratherapeutic暴露与存在剂量依赖的相关性不良事件有关,包括癫痫发作的风险增加。本研究评估的影响食物的相对生物利用度amifampridine健康受试者和通知的条件可以改变曝光。方法:随机、非盲、治疗-周期交叉研究了47个健康男性和女性受试者。受试者被随机分配接受2单剂量口服磷酸amifampridine盐(20毫克每剂基础等价物)美联储或禁食条件下分离洗脱期。血液和尿液样本进行药代动力学分析之前和之后的剂量。等离子amifampridine和一个不活动的3-N-acetyl代谢物的浓度测定。amifampridine和代谢物的相对生物利用度值评估基于等离子体PK参数AUC0-infinity AUC0-t, Cmax美联储和禁食状态使用noncompartmental药代动力学分析。父母药物和代谢物排出尿浓度的计算。将建立一个食物影响生物利用度的90%可信区间的比例人口AUC0-infinity的几何平均值,AUC0-t或Cmax美联储和禁食政府之间并不是生物等效性范围内的80%到125%。 Tolerability was assessed based on adverse-event reporting, clinical laboratory assessments, physical examination including vital sign measurements, 12-lead ECG, and concurrent medication use. FINDINGS: Food slowed and somewhat decreased the absorption of amifampridine. There was a decrease in exposure (Cmax, 44%; AUC, 20%) after oral administration of amifampridine phosphate salt in the presence of food, and mean Tmax was 2-fold longer in the fed state. The extent of exposure and plasma elimination half-life of the major metabolite was greater than those of amifampridine in the fed and fasted conditions. Mean AUCs in the fed and fasted states were slightly greater in women than men, with no difference in mean Cmax. Orally administered amifampridine was renally eliminated (>93%) as the parent compound and metabolite within 24 hours. Single oral doses of 20 mg of amifampridine phosphate salt were considered well tolerated in both the fed and fasted conditions. High intersubject variability (%CVs, >30%) in amifampridine pharmacokinetic parameter values was observed. IMPLICATIONS: At the intended dose under fasting conditions, amifampridine exposure may be increased. European Union Drug Regulating Authorities Clinical Trials identifier: 2011-000596-13.

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