Assessment of the cardiac safety of fampridine-SR sustained-release tablets in a thorough QT/QTc evaluation at therapeutic and supratherapeutic doses in healthy individuals.
OBJECTIVE
To characterize the effects of a sustained-release formulation of fampridine (fampridine-SR) on QT interval in healthy subjects.


METHODS
In a double-blind, double-dummy trial, healthy subjects were randomized to 5 days treatment with fampridine-SR at therapeutic (10 mg twice daily) or supratherapeutic (30 mg twice daily) doses, placebo or moxifloxacin (400 mg on treatment day 5). Digital 12-lead electrocardiograms were recorded before treatment and on day 5; blood samples determined fampridine concentrations. Central tendency analysis determined whether the upper limit of the CI for the QT (individual-corrected QT; QTcI) interval change exceeded 10 ms. Outlier analysis determined new-onset QT (corrected QT; QTc) intervals; maximum change in QTc from baseline of 30 - 60 ms and maximum change from baseline >or= 60 ms. The relationship between pharmacokinetic parameters and QTcI values is explored.


RESULTS
Moxifloxacin was associated with a QTcI interval increase > 5 ms at 7 time points; no increase was observed with either dose of fampridine-SR; there were no fampridine outliers. Pharmacokinetic evaluation failed to find dose-dependent cardiac effects. Fampridine was well tolerated, with a higher frequency of adverse events at the supratherapeutic dose.


CONCLUSIONS
This study showed that fampridine-SR at therapeutic and supratherapeutic doses was not associated with QT prolongation in healthy subjects.
March
Barrie
B
PRACS Institute, Ltd, Fargo, ND 58104, USA. Barrie.March@cetero.com
Cardi
Tara
T
D015761:4-Aminopyridine / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000009:adverse effects; D001372:Aza Compounds / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D008297:Male; D000077266:Moxifloxacin; D026902:Potassium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood; D011804:Quinolines / Q000009:adverse effects
D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D026902:Potassium Channel Blockers; D011804:Quinolines; D015761:4-Aminopyridine; D000077266:Moxifloxacin