Establishment of Retigabine Safety and Tolerability: An Ascending, Multiple Dose Study in Healthy Volunteers
Abstract number :
3.185
Submission category :
Year :
2000
Submission ID :
809
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Jeffrey Paul, Geraldine M Ferron, Steve M Troy, Lyette S Richards, Richard J Fruncillo, John A Getsy, Wyeth-Ayerst Research, Radnor, PA; Graduate Hosp, Philadelphia, PA.
RATIONALE: Retigabine, a potent anticonvulsant in a broad range of experimental seizure models, has novel K+ channel opening and GABAergic properties. The primary purpose of this study was to identify the maximum tolerated dose (MTD) in healthy volunteers for use in future dose ranging epilepsy studies. METHODS: Male volunteers (n=45), 9 subjects/dose group, were randomly assigned to receive either placebo (n=3) or retigabine (n=6), given every 12 hours (q12h) for 14 days (single doses on day 1 and 15). Fixed doses (200, 400, 500 and 600 mg/day) were given to the first 4 groups in a sequential parallel design. The last group received 200 mg of retigabine initially, then titrated every 4 days until a dose of 700 mg/day was reached on day 12. Serial blood samples were collected for pharmacokinetic evaluation on days 1 and 15. Safety was assessed from reported adverse events (AEs), physical examinations, clinical labs, serial electrocardiograms (EKG), and vital signs. RESULTS: There were no serious AEs. The AEs were mild to moderate and were generally limited to CNS. Most AEs were transient, disappearing after the first day. The AEs responsible for limiting dose escalation in the fixed dose groups were related to CNS and GI. No dose-response or accumulation effects were observed regarding laboratory tests and vital signs. There were no drug-related changes in ECG PR, QRS, or QTc intervals, or heart rate. The fixed dose MTD, based on reported AEs was 250 mg q12h. In the dose-titration group, subjects reached 350 mg, q12h, without any dose-limiting AEs. Retigabine was rapidly absorbed and eliminated with a mean terminal half-life of 8.0 hours. The single-dose and steady-state pharmacokinetics of retigabine were linearly dose proportional and in agreement. CONCLUSIONS: Retigabine was well tolerated, with no serious AEs when given q12h for 14 days. The MTD in the fixed dose regimen was 250 mg, q12h. Since the MTD was not reached in the titration regimen, it suggests that future studies with dose titration in epileptic patients will be well tolerated.