Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers
Pharmacokinetics and safety of 3,4-diaminopyridine base in healthy Japanese volunteers
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DOI：
10.5414/cp202133
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发表时间：
2015-08-01
影响因子：
0.8
通讯作者：
Komai, Kiyonobu
中科院分区：
文献类型：
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作者：
Ishida, Natsuko;Kobayashi, Erina;Komai, Kiyonobu
目的：3，4-二氨基吡啶（3，4-DAP）常用于治疗神经肌肉疾病，如Lambert-Eaton肌无力综合征，但3，4-DAP碱的药代动力学尚未研究。因此，我们在日本健康志愿者中研究了3，4-DAP碱的药代动力学。材料与方法：在这项交叉研究中，我们对日本健康志愿者（n = 5）在进食后单次口服10或20 mg 3，4-DAP碱，或对空腹个体单次口服10 mg 3，4-DAP。我们测量血清3，4-DAP浓度，进行心电图（ECG），并进行问卷调查。结果如下：进食后给予10或20 mg 3，4-DAP后，最大血清浓度（C-max）分别为8.09 +/- 4.47 ng/mL和35.8 +/- 15.7 ng/mL（平均值+/-标准差;血清浓度-时间曲线下面积（外推至无穷大）分别为639 +/- 213 ngxmin/mL和2，097 +/- 936 ngxmin/mL（平均值+/- SD）。对禁食个体的给药表明，食物摄入不会显著改变3，4-DAP的药代动力学。ECG显示无临床显著变化，但所有病例的PR间期均延长。5例受试者中有2例在给予20 mg 3，4-DAP后出现口周感觉异常症状。结论：3，4-DAP碱的药代动力学呈非线性。尽管未观察到ECG的临床显著变化，但建议在3，4-DAP给药期间定期进行ECG，以监测心脏功能。此外，口周感觉异常的发生可能取决于所用3，4-DAP的剂量。
Objective: 3,4-diaminopyridine (3,4-DAP) is commonly used for treating neuromuscular diseases, such as the Lambert-Eaton myasthenic syndrome, but the pharmacokinetics of 3,4-DAP base have not been investigated. We therefore studied 3,4-DAP base pharmacokinetics in healthy Japanese volunteers. Materials and methods: In this crossover study, we administered a single oral dose of 10 or 20 mg 3,4-DAP base to healthy Japanese volunteers (n = 5) after food intake, or 10 mg 3,4-DAP to fasting individuals. We measured serum 3,4-DAP concentrations, performed electrocardiography (ECG), and administered questionnaires. Results: After administration of 10 or 20 mg 3,4-DAP following food intake, the maximum serum concentrations (C-max) were 8.09 +/- 4.47 ng/mL and 35.8 +/- 15.7 ng/mL, respectively (mean +/- standard deviation; SD), and the areas under the serum concentration-time curve (extrapolated to infinity) were 639 +/- 213 ngxmin/mL and 2,097 +/- 936 ngxmin/mL (mean +/- SD), respectively. Administration to fasted individuals indicated that food intake did not significantly alter 3,4-DAP pharmacokinetics. ECG showed no clinically significant changes, but PR intervals were prolonged in all cases. Two out of 5 subjects showed perioral paresthesia symptoms after administration of 20 mg 3,4-DAP. Conclusion: This study indicated that 3,4-DAP base pharmacokinetics were non-linear. Although no clinically significant changes in ECG were observed, it is advisable to perform ECG periodically during 3,4-DAP administration in order to monitor cardiac function. Moreover, the development of perioral paresthesia may be dependent on the dose of 3,4-DAP used.