Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury

Objective: To examine the pharmacokinetics and safety of sustained-release 4-aminopyridine (Fampridine-SR), a potassium channel blocker, in subjects with chronic, incomplete spinal cord injury (SCI). Design: Open-label. Setting: Clinical research unit in Ontario. Participants: Sixteen neurologically stable subjects with chronic, incomplete SCI (American Spinal Injury Association Impairment Scale grade B, C, or D). Intervention: Oral administration of Fampridine-SR (25, 30, 35, 40, 50, 60mg twice daily, each for 1wk). Main Outcome Measures: Steady-state pharmacokinetic parameters: maximum observed plasma concentration (C-max), minimum observed plasma concentration (C-min), average observed plasma concentration (C-av), area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12)), time to C-max (t(max)), plasma half-life (t(1/2)), apparent volume of distribution (V-d/F), and apparent total clearance (Cl/F). Safety assessments: physical examinations, vital sign measurements, clinical laboratory tests, electrocardiogram recordings, and adverse events. Results: Mean steady-state C-max, C-min, C-av, and AUC(0-12) increased over the entire Fampridine-SR dosage range and were dosage dependent up to 50mg twice daily. Fampridine-SR had a mean t(max) of 2.2 to 3.0 hours and a mean t(1/2) of 5.7 to 6.9 hours. Mean V-d/F (415.4-528.0L) and Cl/F (51.4-57.7L/h) were independent of dosage, as were mean t(max) and t(1/2) across dosages. Adverse events were mild or moderate and were not dosage related. During the entire study period (17wk), dizziness was the most frequently reported adverse event, followed by urinary tract infection, paresthesia, ataxia, and insomnia. Conclusion: In subjects with chronic, incomplete SCI, Fampridine-SR was slowly absorbed and eliminated, which will allow Fampridine-SR to be administered in a convenient twice-daily manner. Fampridine-SR was well tolerated at dosages from 25 to 60mg twice daily.