目标:葡糖(MerckHealthcareKGaA,Darmstadt,德国)是盐酸二甲双胍的鼻祖品牌,一种口服抗糖尿病药物。二甲双胍在指南中被推荐作为2型糖尿病的一线治疗,并且越来越多地用于相关的胰岛素抵抗病症。如糖尿病前期和多囊卵巢综合征。Glucophage的GelShield®缓释制剂片剂已从2000年上市的历史版本进行了改进。生物等效性已经在这一演变过程中逐步被证明;然而,缺少初始版本和当前版本之间的头对头评估。本分析旨在缩小这一差距,并确定二甲双胍的相关发起人GelShield®缓释制剂之间的生物等效性。葡糖(GXR500毫克),来自欧洲和美国。
方法:来自来自欧洲的361名亚裔和非亚裔健康参与者的7项随机交叉生物等效性研究的数据,美国,亚洲被认为。所有人在进食和禁食状态的健康男性和女性参与者中评估了500mg测试和参考制剂的单次口服剂量。通过对来自欧洲的当前圆形片剂(rGXREU)和来自美国的历史性长方形片剂(oGXRUS)在健康的亚洲和非亚洲参与者在进食和禁食条件下的可用数据进行组合桥接分析,评估了生物等效性。用AUC0-t的混合效应模型对两种制剂之间的生物等效性进行统计学评估,Cmax,和AUC0-inf。
结果:在所有研究中,显示了GXR的相应测试制剂和参考制剂之间的生物等效性。对2项(主要汇集集)或3项研究(次要汇集集)的汇总药代动力学数据的统计分析表明,rGXREU和oGXRUS之间通过与oGXREU桥接而具有生物等效性。所有药代动力学参数的几何平均比率的90%CI在0.80至1.25的生物等效性范围内。在主池集中,进食组的几何最小二乘平均比值在AUC0-inf的0.9931(90%CI,0.9151-1.0778)至Cmax的1.1344(90%CI,1.0711-1.2014)之间;禁食组的结果相似.二级池化集,增加了一项针对亚洲人的研究,证实了这些发现。
结论:在健康男性和女性中,在禁食和进食条件下,确定了来自欧洲和美国的Glucophagegage的缓释制剂之间的生物等效性,包括不同的种族。随着OGXRUS的发展,可以声称GlucophogeageXR的有效性和安全性,通过OGXREU到RGXREU,在几个种族和生产基地。
OBJECTIVE: GlucophageⓇ (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in guidelines as first-line treatment of type 2 diabetes mellitus and increasingly in related insulin-resistant conditions, such as prediabetes and polycystic ovary syndrome. The GelShieldⓇ sustained-release formulation tablet of GlucophageⓇ has been improved from the historic version marketed in 2000. Bioequivalence has been demonstrated stepwise along this evolution; however, a head-to-head evaluation between the initial and the current version is missing. This analysis aims to close this gap and to determine bioequivalence between related originator GelShieldⓇ sustained-release formulations of metformin, GlucophageⓇ (GXR 500 mg), from Europe and the United States.
METHODS: Data from seven randomized crossover bioequivalence studies in 361 healthy participants of Asian and non-Asian ethnicity from Europe, the United States, and Asia were considered. All evaluated a single oral dose of 500 mg of the test and reference formulation in healthy male and female participants in fed and fasted state. Bioequivalence was evaluated by means of a combined bridging analysis of available data on the current round tablet from Europe (rGXR EU) and the historic oblong tablet from the United States (oGXR US) in healthy Asian and non-Asian participants under fed and fasting conditions. Bioequivalence between the two formulations was assessed statistically with a mixed effects model for AUC0-t, Cmax, and AUC0-inf.
RESULTS: In all studies, bioequivalence between the respective test and reference formulations of GXR was shown. Statistical analysis of pooled pharmacokinetic data of 2 (primary pooling set) or 3 studies (secondary pooling set) demonstrated bioequivalence between rGXR EU and oGXR US via bridging with oGXR EU. The 90% CI for the geometric mean ratio of all pharmacokinetic parameters was within the bioequivalence range of 0.80 to 1.25. In the primary pooling set, geometric least squares mean ratios in the fed group ranged from 0.9931 (90% CI, 0.9151-1.0778) for AUC0-inf to 1.1344 (90% CI, 1.0711-1.2014) for Cmax; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings.
CONCLUSIONS: Bioequivalence was determined between sustained-release formulations of GlucophageⓇ from Europe and the United States under fasted and fed conditions in healthy men and women, including different ethnicities. The efficacy and safety of GlucophageⓇ XR can be claimed along the evolution from oGXR US, via oGXR EU to rGXR EU, and in several ethnicities and production sites.