PURPOSE:To test for bioequivalence of 200 mg lacosamide oral tablet and syrup formulations. Additional objectives were to compare the pharmacokinetic profile of lacosamide in saliva and plasma, and to evaluate its tolerability. METHODS:This open-label, randomized, two-way crossover trial was conducted in 16 healthy Caucasian male participants in Germany. The bioequivalence of 200 mg lacosamide tablet and syrup was evaluated using plasma to determine maximum measured concentration (C(max)) and area under the curve from zero to the last time point (AUC)(0-tz). Plasma and saliva samples for evaluation of pharmacokinetic parameters of lacosamide and the major metabolite O-desmethyl lacosamide (SPM 12809) were taken over 15 time points (0.5-72 h) and used to statistically compare bioavailability of the two. Urine samples were collected predose and over five time points (0-48 h) to evaluate the cumulative amount of unchanged drug and metabolite. KEY FINDINGS:Lacosamide median time to reach C(max) (t(max)) was 1 h for tablet and 0.5 h for syrup in plasma and saliva. Mean terminal half life (t(½)) for tablet and syrup was 12.5 and 12.4 h in plasma, and 13.1 and 13.3 h in saliva, respectively. Tablet and syrup mean plasma AUC(0-tz) was 84.5 and 83.3 μg/mL*h, respectively. Mean AUC(0-tz) in saliva was 93.2 μg/mL*h for tablet and syrup. Mean C(max) for tablet was 5.26 μg/mL in plasma and 5.63 μg/mL in saliva. Syrup mean C(max) was 5.14 and 8.32 μg/mL in plasma and saliva, respectively. Within 2 h of syrup administration, elevated lacosamide concentration in saliva compared to plasma was observed. The ratio of lacosamide syrup to tablet was 0.98 for C(max) and 0.99 for AUC(0-tz) in plasma, and 1.00 for AUC((0-tz)) in saliva; the 90% confidence intervals (CIs) for these parameters were within the range of 0.80-1.25, which meets accepted bioequivalence criteria. The syrup-to-tablet ratio for C(max) in saliva was 1.48, and the 90% CIs exceeded the accepted upper boundary for bioequivalence (1.32-1.66). Both formulations were well tolerated. Metabolite concentration versus time profiles for saliva were similar to plasma following tablet and syrup administration. SIGNIFICANCE:The tablet and syrup formulations of lacosamide 200 mg were bioequivalent and well tolerated. Saliva samples were demonstrated to be a suitable surrogate to evaluate lacosamide tablet pharmacokinetics in the central compartment. Due to residual syrup in the buccal cavity, limitations exist when using saliva to evaluate the pharmacokinetics of lacosamide syrup <2 h after administration.

译文

目的:测试200毫克拉考酰胺口服片剂和糖浆制剂的生物等效性。其他目标是比较拉可酰胺在唾液和血浆中的药代动力学特征,并评估其耐受性。
方法:这项开放标签,随机,双向交叉试验是在德国的16位健康的白种人男性参与者中进行的。使用血浆评估200 mg拉考酰胺片和糖浆的生物等效性,以确定最大测量浓度(C(max))和从零到最后一个时间点的曲线下面积(AUC)(0-tz)。在15个时间点(0.5-72 h)采集血浆和唾液样品以评估拉可酰胺和主要代谢产物O-去甲基拉可酰胺(SPM 12809)的药代动力学参数,并用于统计学比较两者的生物利用度。在给药前和五个时间点(0-48小时)内收集尿液样品,以评估未改变药物和代谢物的累积量。
主要发现:血浆和唾液中Lacosamide达到C(max)(t(max))的中位时间为1小时,糖浆为0.5小时。片剂和糖浆的平均终末半衰期(t(1/2))在血浆中分别为12.5和12.4 h,在唾液中分别为13.1和13.3 h。片剂和糖浆的平均血浆AUC(0-tz)分别为84.5和83.3μg/ mL * h。片剂和糖浆中唾液的平均AUC(0-tz)为93.2μg/ mL * h。片剂的平均C(max)在血浆中为5.26μg/ mL,在唾液中为5.63μg/ mL。血浆和唾液中糖浆的平均C(max)分别为5.14和8.32μg/ mL。在给予糖浆的2小时内,观察到唾液中拉考酰胺的浓度与血浆相比有所升高。血浆中拉考酰胺糖浆与片剂的比例在血浆中C(max)为0.98,在AUC(0-tz)中为0.99,在唾液中AUC((0-tz))中为1.00。这些参数的90%置信区间(CIs)在0.80-1.25的范围内,符合公认的生物等效性标准。唾液中C(max)的糖浆与片剂之比为1.48,并且90%的CI超过了生物等效性的可接受上限(1.32-1.66)。两种制剂均具有良好的耐受性。片剂和糖浆给药后,唾液的代谢物浓度与时间的关系与血浆相似。
重要性:200毫克拉考酰胺的片剂和糖浆制剂具有生物等效性,并具有良好的耐受性。唾液样品被证明是评估中隔室中拉考酰胺片药代动力学的合适替代品。由于颊腔中残留糖浆,使用唾液评估给药后2小时内的拉考酰胺糖浆的药代动力学存在局限性。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录