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, 60 mg twice daily, each for 1 wk).

MAIN OUTCOME MEASURES

Steady-state pharmacokinetic parameters: maximum observed plasma concentration (Cmax), minimum observed plasma concentration (Cmin), average observed plasma concentration (Cav), area under the plasma concentration-time curve from 0 to 12 hours (AUC(0-12)), time to Cmax (tmax), plasma half-life (t(1/2)), apparent volume of distribution (Vd/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 Cmax, Cmin, Cav, and AUC(0-12) increased over the entire Fampridine-SR dosage range and were dosage dependent up to 50 mg twice daily. Fampridine-SR had a mean tmax of 2.2 to 3.0 hours and a mean t(1/2) of 5.7 to 6.9 hours. Mean Vd/F (415.4-528.0 L) and Cl/F (51.4-57.7 L/h) were independent of dosage, as were mean tmax and t(1/2) across dosages. Adverse events were mild or moderate and were not dosage related. During the entire study period (17 wk), 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 60 mg twice daily.