Kim Kyu-Pyo, Lim Kyoung Soo, Kim Bo-Hyung, Shin Hyun-Suk, Cho Joo-Youn, Shin Sang-Goo, Jang In-Jin, Yu Kyung-Sang
Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
Int J Clin Pharmacol Ther. 2012 Feb;50(2):142-9. doi: 10.5414/cp201598.
Pharmacokinetic (PK) profiles of glimepiride and metformin have been established for the combination drug as well as each agent individually. However, the PK profiles of a combination drug containing glimepiride and sustained-release (SR) metformin have not been reported. To compare the pharmacokinetic profiles of glimepiride/SR metformin (2 mg/500 mg) with the PK of immediate-release (IR) formulations, an open-label, randomized, 3-period, 3-sequence, 3-treatment, crossover study was conducted in 12 healthy subjects.
After a single administration of glimepiride/SR metformin 2 mg/500 mg (Treatment) or glimepiride/metformin IR 2 mg/500 mg (Reference 1), or administration of 2 doses of glimepiride/metformin IR 1 mg/250 mg 12 h apart (Reference 2), serial blood samples were collected and drug concentrations determined by liquid chromatography/ tandem mass spectrometry. PK parameters (Cmax and AUC24) for glimepiride and metformin were log-transformed and compared using a mixed-effects model analysis of variance (ANOVA). The mean differences and 95% confidence intervals (CIs) were back-transformed to obtain geometric mean ratios along with the CIs for the ratios.
Treatment demonstrated similar systemic exposures for glimepiride; the geometric mean ratio (95% CIs) for glimepiride AUC24 was 1.05 (0.97 - 1.13) for Treatment relative to Reference 1 and 1.08 (1.00 - 1.17) for Treatment relative to Reference 2. The SR formulation showed a delay in the time to reach maximum concentration for metformin from 1.0 - 4.0 h to 4.0 - 8.0 h and a decreased AUC24 value; the geometric mean ratio for metformin AUC24 was 0.87 (0.74 - 1.03) for Treatment relative to Reference 1 and 0.75 (0.63 - 0.88) for Treatment relative to Reference 2.
This study demonstrates for the first time that fixed-dose glimepiride and SR metformin 2 mg/500 mg shows a PK profile similar to that of glimepiride, but with a delayed time to maximum concentration and slightly decreased bioavailability for metformin compared with the IR fixed-dose combination, in healthy volunteers. PK profiles from this exploratory study will be helpful in designing and conducting further studies in diabetic patients.
已确定了联合药物中格列美脲和二甲双胍以及每种药物单独使用时的药代动力学（PK）特征。然而，含有格列美脲和缓释（SR）二甲双胍的联合药物的PK特征尚未见报道。为比较格列美脲/ SR二甲双胍（2 mg/500 mg）与速释（IR）制剂的PK特征，在12名健康受试者中进行了一项开放标签、随机、3期、3序列、3治疗的交叉研究。
单次给予格列美脲/ SR二甲双胍2 mg/500 mg（治疗组）或格列美脲/二甲双胍IR 2 mg/500 mg（参比1），或间隔12小时给予2剂格列美脲/二甲双胍IR 1 mg/250 mg（参比2）后，采集系列血样，采用液相色谱/串联质谱法测定药物浓度。对格列美脲和二甲双胍的PK参数（Cmax和AUC24）进行对数转换，采用混合效应方差分析（ANOVA）进行比较。将平均差值和95%置信区间（CI）进行逆转换，以获得几何平均比值及其CI。
治疗组格列美脲的全身暴露量相似；治疗组相对于参比1的格列美脲AUC24几何平均比值（95%CI）为1.05（0.97 - 1.13），相对于参比2为1.08（1.00 - 1.17）。SR制剂使二甲双胍达到最大浓度的时间从1.0 - 4.0小时延迟至4.0 - 8.0小时，且AUC24值降低；治疗组相对于参比1的二甲双胍AUC24几何平均比值为0.87（0.74 - 1.03），相对于参比2为0.75（0.63 - 0.88）。
本研究首次表明，固定剂量的格列美脲和SR二甲双胍2 mg/500 mg在健康志愿者中的PK特征与格列美脲相似，但与IR固定剂量组合相比，二甲双胍达到最大浓度的时间延迟，生物利用度略有降低。这项探索性研究的PK特征将有助于设计和开展针对糖尿病患者的进一步研究。
