摘要
目的建立有限采样法估算环孢素(CsA)的药动学参数mρax和AUC0-t,并对两种CsA微乳制剂进行生物等效性评价。方法采用2周期双交叉的试验设计,20名健康志愿者poCsA微乳参比制剂和受试制剂500 mg。高效液相色谱法测定各采样时间点CsA的血药浓度。以参比制剂血药浓度数据作为建模数据,以稀疏血药浓度数据点建立多元回归数学模型,估算mρax和AUC0-t。内部验证采用Jacknife法,外部验证以受试制剂数据和MonteCarlo法生成的模拟数据进行。最后采用参数的模型估算值进行生物等效性评价,并与经典方法比较。结果2个和3个血药浓度数据点预测的药动学参数回归模型的线性关系较好(r2>0.85),内部和外部验证表明,给药后1.5和6 h血药浓度(1ρ.5,6ρ)估算mρax的准确性较好,1ρ.5,6ρ,1ρ2估算AUC0t-的准确性较好(平均预测误差<4%、平均绝对误差<8%、标准差<10%),有限采样法评价生物等效性与经典生物等效性研究方法的评价结果无显著性差异(P<0.05)。结论有限采样法估算口服CsA微乳制剂生物等效性是可行的,为该法应用于体内药动学个体差异较大的药物生物等效性研究提供有利的证据。
OBJECTIVE To develop limited sampling strategies （LSS） for estimating cyclosporin A （CsA） microemulsion bioequivalence parameters ρmax and AUC0-t, and assess the bioequivalence of CsA microemulsion by LSS model. METHODS Healthy subjects （n =20） ,enrolled in a bioequivalence study,were administered orally reference and test formulation of 500 mg CsA microemulsion. The whole blood concentration of CsA was determined by the validated HPLC method. A multiple linear regression analysis was developed for estimating ρmax and AUC0-t using the CsA concentration of the reference formulation to develop LSS models. The LSS models were internally validated by the Jacknife method. The models were also externally validated by test formulation and simulated sets generated by Monte Carlo simulation. Bioequivalence assessment of the CsA microemulsion, based on LSS-derived ρmax and AUC0-t values,was identified to those obtained using traditional method. RESULTS The linearity relationship between parameters and single concentration point was poor. Several models for these parameters estimation met the predefined criteria （r^2 〉0. 85）. Validation tests indicated that most informative sampling points （ρ1,5 ,ρ6 for ρmax ,ρ1,5 ,ρ6 ,ρ12 for AUC0-t ） provided accurate estimations of these parameters （Mean prediction error 〈 4%, Mean absolute percentage 〈 8%, standard deviation 〈 10% ）. Bioequivalence assessment results showed that LSS models provided correct assessment of bioequivalence between two CsA microemulsion （P 〈 0. 05）. CONCLUSION LSS model is built for bioequivalence assessment of CsA preparations. The method is accuracy and can be considered desirable for CsA bioequivalence study.
出处
《中国药学杂志》
CAS
CSCD
北大核心
2007年第4期283-288,共6页
Chinese Pharmaceutical Journal
