Pharmacokinetics and tolerability of single escalating doses of fampridine sustained-release tablets in patients with multiple sclerosis: a Phase I-II, open-label trial.

BACKGROUND

Fampridine (4-aminopyridine) is a potassium channel-blocking agent that has been reported to have therapeutic potential for improving walking and mobility in patients with multiple sclerosis (MS). A sustained-release (SR) formulation of fampridine was developed to improve the agent's pharmacokinetic profile by extending its t((1/2)) relative to that of immediate-release fampridine.

OBJECTIVES

The primary study objective was to examine the pharmacokinetics of fampridine SR tablets after single escalating doses in patients with MS. Tolerability was evaluated as a secondary end point.

METHODS

This multicenter, Phase I-II, open-label trial evaluated the dose proportionality and tolerability of 4 single doses of fampridine SR (5, 10, 15, and 20 mg) in patients with MS. There was a 4-day washout between doses. Blood samples were collected immediately before drug administration, hourly for the first 8 hours after administration, and at 10, 12, 14, 18, and 24 hours after administration. The pharmacokinetic parameters evaluated included C(max), T(max), AUC, elimination rate constant, apparent elimination t((1/2)), and apparent CL/F. Twelve-lead ECGs were obtained at baseline (0.5 hour before dosing) and at 1, 4, 12, and 24 hours after drug administration to evaluate potential effects on the QTc interval. All adverse events, abnormal laboratory values, and ECG abnormalities were recorded and evaluated for clinical relevance. Adverse-event data were monitored for 24 hours after the last dose, and patients were instructed to report any adverse events for 14 days after the conclusion of the study.

RESULTS

Twenty-four white patients were enrolled (58% female; mean [SD] age, 45.4 [7.3] years; weight range, 47.8-87.1 kg), and 23 completed the study. Mean plasma concentrations and AUC values were dose proportional. T(max) occurred at 3.36 to 3.92 hours after dosing; the apparent elimination t((1/2)) was 5.47 hours. Both sex and weight affected the pharmacokinetic parameters of fampridine SR. Eleven treament-related adverse events were reported in 10 patients, with dizziness being the most common (7 incidents reported by 6 patients [1 at 10 mg, 3 at 15 mg, and 3 at 20 mg]). Other adverse events included amblyopia, asthenia, headache, and ataxia. All treatment-related adverse events were mild to moderate in severity, with the exception of 1 case of dizziness (20 mg) that was considered severe. No serious adverse events were reported, and no clinically significant changes in corrected QT intervals were observed. No patients with-drew due to treatment-related adverse events.

CONCLUSION

In these patients with MS, fampridine SR (5-20 mg) had a potentially advantageous pharmacokinetic profile relative to that associated with immediate-release fampridine and was generally well tolerated.