摘要
目的建立有限采样法模型估算盐酸吡格列酮(PGT)制剂的生物等效性。方法以健康志愿者口服PGT参比制剂后的血药浓度数据建模,有限采样法建立多元回归模型估算Cm ax和AUC0-t。模型的内部和外部验证分别以Jackkn ife法和Monte Carlo法生成的模拟数据进行。选择最佳模型进行生物等效性评价。结果给药后1.5 h和2.5 h血药浓度(C1.5和C2.5)估算Cm ax的准确性较好,C1.5和C9估算AUC0-t的准确性较好,平均预测误差<5%、平均绝对误差<9%,参数预测误差超过±20%的样本数<5%。生物等效性评价结果与经典法一致。结论有限采样法估算口服PGT制剂的生物等效性是可行的,为生物等效性研究提供新的思路和方法。
Aim To develop limited sampling strategy （LSS） for estimation of Cmax and AUC0-t, and assessing the bioequivalence of two pioglitazone hydrochloride （PGT） preparations. Methods Healthy subjects （n =20）, enrolled in a bioequivalence study, were received 30 mg PGT po of reference or test formulation. The plasma concentration of PGT was determined by the validated HPLC method. A multiple linear regression analysis of the Cmax and AUC0-t, against the PGT concentration for the reference formulation was carried out to develop LSS models to estimate these parameters. The models were internally validated by the Jackknife method and externally validated using simulated sets generated by Monte Carlo method. The best model was employed to assess bioequivalence of the two PGT formulations. Results The linear relationship between pharmacokinetics parameters and single concentration point was poor. Several models for these parameters estimation met the predefined criteria （r2 〉 0.9）. The Jackknife validation procedure revealed that LSS models based on two sampling times （C1, C2.5 and C1.5, C2.5 for Cmax ; C1.5 , C9 and C25 , C9 for AUC0-t） predict accurately. Mean prediction errors （MPE） were less than 3% , and mean absolute prediction error （MAE） were less than 9%. The prediction error （PE） beyond 20% was less than 5% of total samples. Model external validation by Monte Carlo simulated data indicated that the most informative sampling combinations were C1.5, C25 for C and C1.5, C9 for AUC0-t, respectively. MPE and MAE of the proposed models were less than 5% , and 9% respectively. The PE beyond 20% was less than 5% of the total. Bioequivalence assessment of the two PGT 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 PGT formulations were bioequivalent. Conclusion The LSS method for bioequivalence assessment of PGT formulations was established and proved to be applicable and accurate. Thus, it could be considered appropriate for PGT bioequivalence study with inexpensive cost of sampling acquisition and analysis.
出处
《药学学报》
CAS
CSCD
北大核心
2006年第9期893-898,共6页
Acta Pharmaceutica Sinica
