Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
Clin Ther. 2012 May;34(5):1056-69. doi: 10.1016/j.clinthera.2012.03.007. Epub 2012 Apr 11.
Dalfampridine (fampridine outside the United States) is a broad-spectrum potassium channel blocker. Dalfampridine extended-release tablets have been approved by the US Food and Drug Administration to improve walking in patients with multiple sclerosis (MS).
The objective of this article is to review the safety profile of dalfampridine extended-release tablets with respect to its expected use in patients with MS.
We reviewed published data relevant to patient safety profiles based on searches of articles in PubMed published up to December 31, 2010, using the search terms fampridine OR dalfampridine OR 4-aminopyridine AND (multiple sclerosis) in combination with toxicity, safety, clinical trial, pharmacokinetics, and seizures. These searches were supplemented with data derived from the approved package insert and relevant sections of the New Drug Application (22-250) as submitted to the US Food and Drug Administration.
The literature searches returned 58 unique citations, of which 26 were considered relevant for characterizing the safety profile of dalfampridine; excluded citations were as follows: reviews (19), evaluation of 3,4-diaminopyridine (4), intravenous dosing (2), inadequate information on patient doses (2), preclinical models (2), and "other" (3). Dalfampridine is nearly completely (approximately 96%) eliminated unchanged in urine, with limited transformation to 2 inactive metabolites and low risk for interaction with drugs metabolized by hepatic P450 cytochromes. However, in patients with renal impairment (creatinine clearance [CrCl], ≤80 mL/min), mean peak plasma concentrations were 68%-101% higher and apparent clearance was 43%-73% lower relative to those without impairment, precluding dalfampridine use in patients with moderate (CrCl, 30-50 mL/min) or severe renal impairment (CrCl, <30 mL/min). Dalfampridine has a narrow therapeutic range. At the therapeutic dose of 10 mg twice daily, adverse events were generally mild to moderate and, consistent with the mechanism of action of dalfampridine, were primarily related to stimulatory effects on the nervous system. A thorough QT study suggested a low risk of induction of QT prolongation and associated cardiac arrhythmias in healthy individuals at therapeutic (10 mg, twice daily) or supratherapeutic (30 mg, twice daily) doses. Although the incidence of seizures was dose related, data from the clinical trials of dalfampridine extended-release tablets suggest that the risk of seizure at the therapeutic dose, in patients with no history of seizure, is not likely to be higher than background rates in MS.
In patients with MS, dalfampridine has a narrow therapeutic range but an acceptable safety profile when used at the therapeutic dose of 10 mg twice daily.
地夫可特（美国以外的译名是：盐酸苯海索）是一种广谱钾通道阻滞剂。地夫可特缓释片已获得美国食品药品监督管理局批准，用于改善多发性硬化症（MS）患者的行走能力。
本文旨在回顾地夫可特缓释片的安全性概况，以期了解其在 MS 患者中的预期用途。
我们根据 PubMed 中发表的文章，检索了截至 2010 年 12 月 31 日的相关文献，检索词为：fampridine 或 dalfampridine 或 4-aminopyridine 及（multiple sclerosis），结合了毒性、安全性、临床试验、药代动力学和癫痫发作等方面的内容。这些检索结果补充了从已批准的药品说明书和向美国食品药品监督管理局提交的新药申请（22-250）中获得的数据。
文献检索共返回 58 个独特的引文，其中 26 个被认为与地夫可特的安全性概况有关；排除的引文如下：综述（19 个）、3,4-二氨基吡啶评价（4 个）、静脉给药（2 个）、患者剂量信息不足（2 个）、临床前模型（2 个）和“其他”（3 个）。地夫可特几乎完全（约 96%）以原形经尿液排泄，仅有有限的转化为 2 种无活性代谢物，与经肝 P450 细胞色素代谢的药物相互作用的风险较低。然而，在肾功能损害（肌酐清除率 [CrCl]，≤80 mL/min）患者中，相对于无损害者，地夫可特的平均峰值血浆浓度升高 68%-101%，而表观清除率降低 43%-73%，因此不建议在中度（CrCl，30-50 mL/min）或重度肾功能损害（CrCl，<30 mL/min）患者中使用。地夫可特的治疗窗较窄。在治疗剂量 10mg 每日 2 次时，不良事件通常为轻至中度，且与地夫可特的作用机制一致，主要与对神经系统的刺激作用有关。一项全面的 QT 研究表明，在健康个体中，以治疗剂量（10mg，每日 2 次）或超治疗剂量（30mg，每日 2 次）使用时，地夫可特引发 QT 延长和相关心律失常的风险较低。虽然癫痫发作的发生率与剂量有关，但地夫可特缓释片的临床试验数据表明，在无癫痫发作史的患者中，治疗剂量（每日 10mg，每日 2 次）下发生癫痫的风险不太可能高于 MS 中的背景发生率。
在 MS 患者中，地夫可特的治疗窗较窄，但以 10mg 每日 2 次的治疗剂量使用时，安全性良好。
