空腹口服拉科酰胺片的人体生物等效性
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摘要
目的:研究空腹条件下单次口服国产与进口拉科酰胺片在中国健康受试者中的生物等效性。方法:本试验为随机、开放性研究,采用2制剂、2周期、2序列、自身交叉设计。依据试验方案纳入24例健康受试者,其中男性18例,女性6例。在空腹条件下单次口服受试制剂或参比制剂后,采用液相色谱串联质谱(LC-MS/MS)法测定血浆中拉科酰胺的浓度。使用非房室模型和软件WinNonlin 6. 3计算药动学参数AUC0-t,AUC0-∞,C_(max)和T_(max),以(1～2α)置信区间进行生物等效性评价。结果:本研究共筛选36例受试者,24例受试者筛选合格并入组,其中男性16例,女性8例。24例受试者均完成研究,并进入药动学分析和等效性判断。受试制剂与参比制剂药动学参数(AUC0-t,AUC0-∞和C_(max))几何均值比值的90%置信区间在80. 00%～125. 00%范围内。T_(max)非参数检验结果显示两制剂间没有统计学差异。结论:国产与进口拉科酰胺片(100mg)空腹口服具有生物等效性。
Objective: To explore the bioequivalence of domestic and imported lacosamide(LCM) tablets under fasting condition. Methods: Two formulations, randomized, two-period crossover clinical trials were performed. Twenty-four healthy volunteers were recruited and given a single oral dose of 100 mg of domestic and imported lancosamide tablets under fasting condition. Concentrations of lancosamide in plasma were determined by LC-MS/MS. The 90% confidence intervals(90% CIs) of the test-to-reference geometric mean ratio(GMR) of AUC and C_(max)were calculated to assess the bioequivalence. Results: A total of 36 subjects were screened in this study. 24 of them were selected as eligible subjects for formal test,including 16 males and 8 females. All of the 24 subjects completed the study and entered the pharmacokinetic analysis and equivalence judgment. The 90% CIs of the GMR of AUC0-t,AUC0-∞and C_(max)between the test and reference preparations fell within the limit ranges of80. 00% ～ 125. 00%. The results of T_(max)nonparametric test showed no significant difference between the two preparations. Conclusion: The domestic lancosamide tablets are proved to be bioequivalent to imported lancosamide tablets under fasting condition.
Objective: To explore the bioequivalence of domestic and imported lacosamide(LCM) tablets under fasting condition. Methods: Two formulations, randomized, two-period crossover clinical trials were performed. Twenty-four healthy volunteers were recruited and given a single oral dose of 100 mg of domestic and imported lancosamide tablets under fasting condition. Concentrations of lancosamide in plasma were determined by LC-MS/MS. The 90% confidence intervals(90% CIs) of the test-to-reference geometric mean ratio(GMR) of AUC and C_(max)were calculated to assess the bioequivalence. Results: A total of 36 subjects were screened in this study. 24 of them were selected as eligible subjects for formal test,including 16 males and 8 females. All of the 24 subjects completed the study and entered the pharmacokinetic analysis and equivalence judgment. The 90% CIs of the GMR of AUC0-t,AUC0-∞and C_(max)between the test and reference preparations fell within the limit ranges of80. 00% ～ 125. 00%. The results of T_(max)nonparametric test showed no significant difference between the two preparations. Conclusion: The domestic lancosamide tablets are proved to be bioequivalent to imported lancosamide tablets under fasting condition.
引文
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[3] Center for drug evaluation,research. Bioequivalence studies with pharmacokinetic end-points for drugs submitted under an ANDA(Draft Guidance)[EB/OL].[2017-04-07]. http://www.fda. gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm377465. pdf.
[4]国家食品药品监督管理总局.以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则[S].2016.
[5] CAWELLO W,BONN R,BOEKENS H. Bioequivalence of intravenous and oral formulations of the antiepileptic drug lacosamide[J]. Pharmacology,2012,90(1-2):40-46.
[6] CAWELLO W,BKENS H,NICKEL B,et al. Tolerability,pharmacokinetics,and bioequivalence of the tablet and syrup formulations of lacosamide in plasma,saliva,and urine:saliva as a surrogate of pharmacokinetics in the central compartment[J]. Epilepsia,2013,54(1):81-88.
[2] CHUNG S,SPERLING MR,BITON V,et al. Lacosamide as adjunctive therapy for partial-onset seizures:a randomized controlled trial[J]. Epilepsia,2010,51(6):958-967.
[3] Center for drug evaluation,research. Bioequivalence studies with pharmacokinetic end-points for drugs submitted under an ANDA(Draft Guidance)[EB/OL].[2017-04-07]. http://www.fda. gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm377465. pdf.
[4]国家食品药品监督管理总局.以药动学参数为终点评价指标的化学药物仿制药人体生物等效性研究技术指导原则[S].2016.
[5] CAWELLO W,BONN R,BOEKENS H. Bioequivalence of intravenous and oral formulations of the antiepileptic drug lacosamide[J]. Pharmacology,2012,90(1-2):40-46.
[6] CAWELLO W,BKENS H,NICKEL B,et al. Tolerability,pharmacokinetics,and bioequivalence of the tablet and syrup formulations of lacosamide in plasma,saliva,and urine:saliva as a surrogate of pharmacokinetics in the central compartment[J]. Epilepsia,2013,54(1):81-88.