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首页> 外文期刊>Journal of Clinical Pharmacy and Therapeutics >Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects
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Investigation of bioequivalence of a new fixed-dose combination of acarbose and metformin with the corresponding loose combination as well as the drug-drug interaction potential between both drugs in healthy adult male subjects

机译：阿卡波糖和二甲双胍新固定剂量组合与相应松散组合的生物等效性研究以及两种药物在健康成年男性受试者中的药物相互作用潜力

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What is known and objective Both metformin and acarbose are recommended monotherapy and add-on therapy in type 2 diabetes mellitus (T2DM). A fixed-dose combination (FDC) of acarbose and metformin has been developed to reduce pill burden and potentially improve compliance. The current study investigated the bioequivalence of the acarbose/metformin FDC compared with the individual agents administered simultaneously (loose combination). Secondary endpoints were the safety and tolerability of the FDC and the potential for drug-drug interactions between acarbose and metformin. Methods A single-centre, randomized, open-label, four-period crossover study was conducted in healthy male Korean subjects aged 18-45 years. Following one-period balanced Williams design, participants were randomized to receive four single oral treatments on different study days separated by ≥7 days' washout. Treatments were as follows: (i) acarbose/metformin 50/500 mg FDC (test); (ii) acarbose 50 mg and metformin 500 mg as loose combination (reference); (iii) acarbose 50 mg; and (iv) metformin 500 mg. Serial blood samples were taken for glucose and insulin levels for 4 h after a sucrose load on the day before and day of study drug administration. Additionally, serial blood samples were taken for analysis of metformin levels for 24 h after each drug containing metformin. The area under the curve for 4 h post-test (AUC0-4 h) and the maximal serum concentration (C max) of plasma glucose and serum insulin were primary pharmacodynamic (PD) parameters, and Cmax, AUC0-last and AUC for metformin levels were primary pharmacokinetic (PK) parameters. The bioequivalence of the FDC to the loose combination was considered established if the 90% confidence intervals (CIs) of the baseline-adjusted PD parameter ratios (test vs. reference) for plasma glucose and the PK parameter ratios for metformin fell completely within current acceptance limits (0·8- 1·25). Results and discussion Thirty-three of 40 randomized subjects completed the study; five withdrew consent and two discontinued because of adverse events (AEs). The 24-h plasma concentration-time curves of metformin and the 4-h plasma glucose-time curves after acarbose/metformin FDC (test) and acarbose + metformin loose combination (reference) were almost superimposable. The geometric least squares (LS) mean of the RatioAUC and RatioCmax for plasma glucose after the FDC vs. loose combination, and the LS mean of the ratios in metformin AUC, AUC0-last and Cmax were close to unity, and the 90% CI of all these parameters fell within the predefined equivalence range of 0·8-1·25, confirming bioequivalence. The metformin AUC was reduced by 26% and Cmax by 34% after acarbose + metformin compared with metformin alone. Eight subjects (20·0%) reported AEs, but all were mild, and most were gastrointestinal, as expected for these agents. The incidence of AEs was not higher with the combinations vs. monotherapy. What is new and conclusion These data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs. The data demonstrate that the acarbose/metformin FDC is bioequivalent to the loose combination of these agents. Although acarbose slightly reduced the bioavailability of metformin, the accumulated evidence of the efficacy of this combination implies that this is clinically irrelevant. The observed AE profile was consistent with the established knowledge on the safety of the two drugs.
机译：已知和客观的建议在2型糖尿病（T2DM）中推荐二甲双胍和阿卡波糖单一疗法和附加疗法。阿卡波糖和二甲双胍的固定剂量组合（FDC）已被开发出来，以减少药丸负担并潜在地改善依从性。目前的研究调查了阿卡波糖/二甲双胍FDC与同时给药（松散组合）的个体相比的生物等效性。次要终点是FDC的安全性和耐受性以及阿卡波糖和二甲双胍之间药物相互作用的潜力。方法对年龄在18-45岁的健康韩国男性受试者进行了单中心，随机，开放标签，四期交叉研究。按照威廉姆斯（Williams）一期平衡设计后，参与者被随机分配在不同研究日接受≥7天冲洗治疗的四次单次口服治疗。治疗方法如下：（i）阿卡波糖/二甲双胍50/500 mg FDC（测试）; （ii）阿卡波糖50毫克和二甲双胍500毫克为松散组合（参考）; （iii）阿卡波糖50毫克; （iv）二甲双胍500毫克。在研究药物施用的前一天和一天中，在蔗糖负载后4小时，采集连续血样的葡萄糖和胰岛素水平。此外，在每种含二甲双胍的药物用药24小时后，采集连续血样分析二甲双胍水平。试验后4小时（AUC0-4 h）的曲线下面积和血浆葡萄糖和血清胰岛素的最大血清浓度（C max）是主要药效学（PD）参数，二甲双胍的Cmax，AUC0-last和AUC水平是主要的药代动力学（PK）参数。如果血浆葡萄糖的基线调整后的PD参数比率（试验与参考值）的90％置信区间（CI）和二甲双胍的PK参数比率完全落在当前接受范围内，则认为FDC与松散组合具有生物等效性限制（0·8- 1·25）。结果与讨论40位随机受试者中的33位完成了这项研究。 5例因不良事件（AE）撤回了同意，2例终止了停药。阿卡波糖/二甲双胍FDC（测试）和阿卡波糖+二甲双胍松散组合（参考）后的二甲双胍的24小时血浆浓度-时间曲线和四小时血糖时间曲线几乎可以叠加。 FDC与松散组合后血浆葡萄糖的RatioAUC和RatioCmax的几何最小二乘（LS）均值，二甲双胍AUC，AUC0-last和Cmax的比值的LS均值接近于1，CI为90％所有这些参数中的所有一个都落入了预定义的当量范围0·8-1·25，证实了生物等效性。与单独使用二甲双胍相比，阿卡波糖+二甲双胍治疗后二甲双胍的AUC降低了26％，Cmax降低了34％。如这些药物所预期的那样，有八名受试者（20·0％）报告了不良事件，但均为轻度，大多数为胃肠道疾病。与单一疗法相比，联合疗法的不良事件发生率并不更高。新发现和结论这些数据表明，阿卡波糖/二甲双胍FDC与这些药物的松散组合生物等效。尽管阿卡波糖稍微降低了二甲双胍的生物利用度，但这种组合功效的累积证据表明这与临床无关。观察到的AE分布与关于两种药物安全性的既定知识一致。数据表明，阿卡波糖/二甲双胍FDC与这些药物的松散组合生物等效。尽管阿卡波糖稍微降低了二甲双胍的生物利用度，但这种组合功效的累积证据表明这与临床无关。观察到的AE分布与关于两种药物安全性的既定知识一致。

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