The Safety Profile of Dalfampridine Extended Release in Multiple Sclerosis Clinical Trials

• Published in: Clinical therapeutics Vol. 34; no. 5; pp. 1056 - 1069
• Main Authors: Cornblath, David R., MD, Bienen, E. Jay, PhD, Blight, Andrew R., PhD
• Format: Journal Article
• Language: English
• Published: Bridgewater, NJ EM Inc USA 01.05.2012; Elsevier; Elsevier Limited
• Subjects: 4-aminopyridine; 4-Aminopyridine - administration & dosage; 4-Aminopyridine - adverse effects; 4-Aminopyridine - therapeutic use; Biological and medical sciences; Clinical trials; Clinical Trials as Topic; dalfampridine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug therapy; fampridine; Humans; Internal Medicine; Medical Education; Medical sciences; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - physiopathology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Neurology; Pharmaceutical industry; Pharmacology. Drug treatments; Potassium Channel Blockers - administration & dosage; Potassium Channel Blockers - adverse effects; Potassium Channel Blockers - therapeutic use; safety; Tablets; Walking; United States > US; 4-aminopyridine; dalfampridine; fampridine; multiple sclerosis; safety; Human; Nervous system diseases; Multiple sclerosis; Potassium channel antagonist; Controlled release form; Toxicity; Fampridine; Pyridine derivatives; Inflammatory disease; Central nervous system disease; Dosage form; Clinical trial; Safety
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2012.03.007

Abstract Background 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). Objective 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. Methods 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. Results 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. Conclusion 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.