Chen L F, Jiao J J, Zhang C L, Lou J S, Liu C X
Department of Pharmacy, Tianjin Medical University, Tianjin, China.
Int J Clin Pharmacol Ther. 2011 Oct;49(10):629-36. doi: 10.5414/cp201538.
The aim of this study was to develop a limited sampling strategy (LSS) that can be used to assess the bioequivalence of two metformin hydrochloride preparations.
Healthy subjects (n = 20) enrolled in the bioequivalence study received a single oral tablet of 1,000 mg metformin reference formulation or test formulation. The plasma concentration of metformin was determined using a validated HPLC method. A multiple linear regression analysis of the observed metformin Cmax and AUC0-24 versus the concentration of reference formulation was performed to develop LSS models for estimating these parameters. The models were internally validated by the Jackknife method. The best models were employed to assess the bioequivalence of the two metformin formulations.
The linear relationship between pharmacokinetic parameters and a single concentration point was poor. Several models for the estimation of these parameters met the predefined criteria (r2 > 0.9). The Jackknife validation procedure revealed that LSS models based on two sampling times - C1.5 and C2 for Cmax; C4.0 and C10.0 for AUC0-24 - were accurate predictor of Cmax and AUC0-24. Prediction errors (PE) were less than 2%, and absolute prediction errors (AE) were less than 10%. PEs beyond 15% occurred in less than 5% of total samples. The bioequivalence assessment of the two metformin formulations, based on the best LSS models, provided results similar to those obtained using all the observed concentration-time data points, and indicated that the two metformin formulations were bioequivalent.
A LSS method for assessing the bioequivalence of metformin formulations was established and proved to be applicable and accurate. This LSS method could be considered appropriate for a metformin bioequivalence study, providing an inexpensive cost of sampling acquisition and analysis.
本研究的目的是开发一种有限采样策略（LSS），可用于评估两种盐酸二甲双胍制剂的生物等效性。
参与生物等效性研究的健康受试者（n = 20）口服1000 mg二甲双胍参比制剂或受试制剂的单剂量片剂。采用经过验证的高效液相色谱法测定血浆中二甲双胍的浓度。对观察到的二甲双胍Cmax和AUC0-24与参比制剂浓度进行多元线性回归分析，以建立用于估计这些参数的LSS模型。采用留一法对模型进行内部验证。使用最佳模型评估两种二甲双胍制剂的生物等效性。
药代动力学参数与单个浓度点之间的线性关系较差。几种用于估计这些参数的模型符合预定义标准（r2 > 0.9）。留一法验证程序表明，基于两个采样时间的LSS模型——Cmax的C1.5和C2；AUC0-24的C4.0和C10.0——是Cmax和AUC0-24的准确预测指标。预测误差（PE）小于2%，绝对预测误差（AE）小于10%。超过15%的PE出现在不到5%的总样本中。基于最佳LSS模型对两种二甲双胍制剂进行的生物等效性评估，得到的结果与使用所有观察到的浓度-时间数据点得到的结果相似，表明两种二甲双胍制剂具有生物等效性。
建立了一种评估二甲双胍制剂生物等效性的LSS方法，证明该方法适用且准确。这种LSS方法可被认为适用于二甲双胍生物等效性研究，具有采样采集和分析成本低廉的特点。
