Global Biostatistics, Clinical Measurement Sciences, Merck Healthcare KGaA, Darmstadt, Germany.
Global Medical Affairs, Merck Healthcare KGaA, Darmstadt, Germany.
Clin Ther. 2024 May;46(5):389-395. doi: 10.1016/j.clinthera.2024.03.011. Epub 2024 Apr 29.
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.
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 AUC, C, and AUC.
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 AUC to 1.1344 (90% CI, 1.0711-1.2014) for C; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings.
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.
Glucophage（德国达姆施塔特的默克医疗保健有限公司）是盐酸二甲双胍的原研品牌，一种口服抗糖尿病药物。二甲双胍被指南推荐作为 2 型糖尿病的一线治疗药物，并在相关胰岛素抵抗情况下（如糖尿病前期和多囊卵巢综合征）越来越多地使用。Glucophage 的 GelShield 缓释片制剂已经从 2000 年上市的历史版本进行了改进。随着这一演变，逐步证明了生物等效性；然而，原始版本和当前版本之间的头对头评估仍然缺失。本分析旨在弥补这一空白，并确定欧洲和美国的相关原研 GelShield 缓释制剂的二甲双胍（Glucophage，GXR 500mg）之间的生物等效性。
考虑了来自欧洲、美国和亚洲的 361 名健康参与者的 7 项随机交叉生物等效性研究的数据。所有研究均在健康男性和女性参与者的进食和禁食状态下评估了 500mg 测试和参比制剂的单次口服剂量。通过对欧洲当前圆形片剂（rGXR EU）和美国历史长圆形片剂（oGXR US）在健康亚洲和非亚洲参与者中的进食和禁食条件下的可用数据进行综合桥接分析，评估了生物等效性。使用混合效应模型对 AUC、C 和 AUC 进行统计评估，评估两种制剂之间的生物等效性。
在所有研究中，均显示 GXR 的各自测试和参比制剂之间具有生物等效性。通过桥接 oGXR EU，对 2 项（主要合并集）或 3 项研究（次要合并集）的药代动力学数据进行汇总的统计分析表明，rGXR EU 和 oGXR US 之间具有生物等效性。所有药代动力学参数的几何均数比值的 90%置信区间均在 0.80 至 1.25 的生物等效性范围内。在主要合并集中，进食组的几何最小二乘均值比值范围为 AUC 的 0.9931（90%置信区间，0.9151-1.0778）至 C 的 1.1344（90%置信区间，1.0711-1.2014）；空腹组的结果相似。加入亚洲人群研究的次要合并集证实了这些发现。
在健康男性和女性中，包括不同种族，确定了欧洲和美国的 Glucophage 缓释制剂在禁食和进食条件下的生物等效性。Glucophage XR 的疗效和安全性可以从 oGXR US 发展到 oGXR EU，再到 rGXR EU，以及在多个种族和生产地点得到保证。
