Perez-Lloret S, Olmos L, de Mena F, Pieczanski P, Rodriguez Moncalvo J J
Clinical Pharmacology Center (FLENI-mrc/ Centralab CR), Buenos Aires, Argentina.
Arzneimittelforschung. 2012 Oct;62(10):470-6. doi: 10.1055/s-0032-1321859. Epub 2012 Aug 29.
OBEJCTIVE: To compare the bioavailability of two 50-mg lamotrigine dispersible tablet formulations (Epilepax®, Ivax-TEVA Argentina Laboratories, Argentina, as a test formulation, and Lamictal®, GlaxoSmithKline, UK, as a reference formulation) in 24 healthy male volunteers.
This study was a randomized, 2-period, 2-sequence crossover design that was open for subjects and investigators, but blind for the bioanalytical lab. Serum samples were obtained over a 120-h interval. A 9-day wash-out period was allowed between treatments. The concentrations of lamotrigine were analyzed by high-performance liquid chromatography followed by ultraviolet-visible detection. Lamotrigine time-concentrations curves were obtained and the following pharmacokinetic parameters were calculated: AUC0-t, AUC0-inf and Cmax. Bioequivalence was declared if the 90% confidence interval (CI) of the mean test/reference ratios for AUC0-t, AUC0-inf and Cmax were within 80.00-125.00%.
The geometric mean and respective 90% CI of test/reference percent ratios were 100.83% (92.53-107.88%) for AUC0-t, 99.91% (93.79-108.40%) for AUC0-inf, and 95.62% (90.91-100.57%) for Cmax. No serious adverse events were observed. 1 patient reported a mild rash following the administration of each formulation.
This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in this sample of fasting healthy volunteers. These results suggest that bioequivalence studies evaluating 50-mg doses of Lamotrigine are feasible and recommended, since such doses may minimize the risk of severe rash or Stevens-Johnson Syndrome. This study was registered at the Argentinean Clinical Trials National Registry (www.anmat.gov.ar), No 1666/2008.
目的：比较两种50毫克拉莫三嗪分散片制剂（阿根廷Ivax - TEVA实验室生产的Epilepax®作为试验制剂，英国葛兰素史克公司生产的Lamictal®作为参比制剂）在24名健康男性志愿者中的生物利用度。
本研究采用随机、两周期、两序列交叉设计，对受试者和研究者开放，但对生物分析实验室设盲。在120小时的时间间隔内采集血清样本。治疗之间允许有9天的洗脱期。采用高效液相色谱法并结合紫外 - 可见检测法分析拉莫三嗪的浓度。获得拉莫三嗪的时间 - 浓度曲线，并计算以下药代动力学参数：AUC0 - t、AUC0 - inf和Cmax。如果AUC0 - t、AUC0 - inf和Cmax的平均试验/参比比值的90%置信区间（CI）在80.00 - 125.00%之内，则判定为生物等效。
AUC0 - t的试验/参比百分比比值的几何均值及相应的90%CI为100.83%（92.53 - 107.88%），AUC0 - inf为99.91%（93.79 - 108.40%），Cmax为95.62%（90.91 - 100.57%）。未观察到严重不良事件。1名患者在服用每种制剂后均报告有轻度皮疹。
这项单剂量研究发现，在该空腹健康志愿者样本中，试验产品和参比产品符合生物等效性的监管标准。这些结果表明，评估50毫克剂量拉莫三嗪的生物等效性研究是可行的且值得推荐，因为这样的剂量可能会将严重皮疹或史蒂文斯 - 约翰逊综合征的风险降至最低。本研究已在阿根廷临床试验国家注册中心（www.anmat.gov.ar）注册，编号为1666/2008。
