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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers.
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Multiple-dose, linear, dose-proportional pharmacokinetics of retigabine in healthy volunteers.

机译：瑞替加滨在健康志愿者中的多剂量，线性，剂量比例药代动力学。

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摘要

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.
机译：瑞替加滨，一种一流的选择性M-电流钾通道开放剂，是目前正在临床开发中的新型抗癫痫药。这项随机安慰剂对照研究的目的是评估健康男性志愿者中的瑞替加滨口服安全性和药代动力学（N = 45）。受试者在第1天接受一剂，在接下来的14天中每12小时服用一次。前四组给予固定剂量（每天200、400、500和600 mg）。第5组的滴定剂量每4天增加100 mg，在第15天每天达到700 mg。在第1天和第15天收集连续血样。比较各天之间和各剂量组之间的药代动力学参数。单一剂量给药后，瑞替加滨被迅速吸收，最大浓度为387 ng / ml（标准化为100 mg剂量），发生时间为1.5小时。在白人受试者中，瑞替加滨被消除，平均终末半衰期为8.0小时，表观口腔清除率为0.70 L / h / kg。在黑人受试者中，通过体重正常化后，瑞替加滨的清除率和分布量分别降低了25％和30％，从而导致该人群的暴露水平更高。瑞替加滨的药物代谢动力学呈线性剂量比例关系。稳态药代动力学与单剂量药代动力学一致，累积比约为1.5。瑞替加滨和AWD21-360谷底夜间浓度明显低于早晨值（约30％至35％）。与固定剂量方案相比，滴定方案允许更高的剂量。总之，对于每天100至700 mg的剂量，瑞替加滨的药代动力学与剂量成线性比例，并且在多次给药时未改变。

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