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Retigabine, a first-in-class selective M-current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo-controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half-life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabine's pharmocokinetics was linearly dose proportional. Steady-state pharmacokinetics was in agreement with single-dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21-360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed-dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.

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