Pharmacokinetic studies of single and multiple oral doses of fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury.
Fampridine (4-aminopyridine) is a potassium channel blocking agent that restores conduction in demyelinated axons and improves neurologic function in patients with chronic spinal cord injury (SCI). Based on the pharmacokinetic profile of orally administered fampridine, multiple daily doses (4 or more) would need to be taken to sustain its therapeutic effects. Two studies were conducted to determine the pharmacokinetics and safety profile of an oral, sustained-release (SR) formulation of fampridine (fampridine-SR, 10-25 mg) administered as a single dose (n = 14) and twice daily for 1 week (n = 16) in patients with chronic, incomplete SCI. Mean plasma concentrations and area under the plasma concentration-time curve were proportional to the dose administered, whereas other pharmacokinetic parameters were independent of dose. Fampridine-SR was absorbed slowly (peak plasma concentration shortly after dosing, 2.6-3.7 hours) and eliminated (plasma half-life, 5.6-7.6 hours), and reached steady state after 4 days of twice-daily administration. Fampridine-SR was well tolerated, with only mild to moderate adverse events reported, and no serious adverse events. The extended plasma half-life of fampridine-SR allows convenient twice-daily dosing. Clinical trials designed to assess neurologic and functional improvement using fampridine-SR in patients with chronic SCI are currently underway.
Hayes
Keith C
KC
University of Western Ontario and Lawson Health Research Institute, London, Ontario, Canada. kchayes@uwo.ca
Potter
Patrick J
PJ
Hansebout
Robert R
RR
Bugaresti
Joanne M
JM
Hsieh
Jane T C
JT
Nicosia
Sera
S
Katz
Mitchell A
MA
Blight
Andrew R
AR
Cohen
Ron
R
D015761:4-Aminopyridine / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002908:Chronic Disease; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D013119:Spinal Cord Injuries / Q000097:blood* / Q000188:drug therapy*
D003692:Delayed-Action Preparations; D015761:4-Aminopyridine