药动学和药效学方法考察沙丁胺醇报雾剂的生物等效性

 目的以药效学方法评价结果为参照，考察药动学方法评价沙丁胺醇气雾剂生物等效性的适用性。方法采用随机分组、自身对照、开放试验设计，舒喘灵为试验制剂，喘乐宁为参比制剂。轻中度哮喘患者单剂量吸入沙丁胺醇400μg，给药后0，5，10，15，20，30min采血，并在6h内定时测定肺功能指标FEV_1.0，PEF，FVC和FEF_25～75及不良反应指标HR。以HPLC测定血浆药物浓度，非房室模型计算生物利用度参数c_max,t_max,AUC_{0～20 min}和AUC_{0～30 min}，通过双向单侧t检验和90%置信区间评价生物等效性。计算FEV_1.0，FVC，PEF，FEF_25～75改善百分数的最大值与平均值，AUC_ΔFEV1.0＞0，AUC_{ΔFEV1.0＞15%}，t_{ΔFEV1.0(0～15%)}，t_{ΔFEV1.0＞15%}，t_max(FEV1.0)，分别进行配对t检验，并对有显著差异的药效学参数进行多因素方差分析。结果两种制剂的c_max分别为(1.22±0.73)和(0.98±0.52 ) ng·mL^-1，t_max分别为(0.21±0.09)和(0.26±0.08) h。AUC_{0～20 min}分别为(0.25±0.10)和(0.18±0.10) ng·h·mL^-1。舒喘灵相对于喘乐宁的生物利用度为63%(90% CI 45%～88%)。双向单侧t检验和90%置信区间显示两种沙丁胺醇气雾剂生物不等效。两种制剂的药效学指标AUC_ΔFEV1.0＞0，AUC_{ΔFEV1.0＞15%}，ΔFEV_1.0(mean)，t_{ΔFEV1.0＞15%}，ΔPEF(max)，ΔHR(mean)有显著差异。舒喘灵的扩支气管作用仅为喘乐宁的70%左右。方差分析显示两种制剂药效学不等效。结论在评价沙丁胺醇气雾剂的生物等效性方面，药动学方法能够得出与药效学方法一致的结论，提示该方法适用于沙丁胺醇气雾剂生物等效性评价。

Bioequivalence evaluation of two salbutamol MDIs in asthmatic patients by pharmacokinetic and pharmacodynamic methods

OBJECTIVE To study the suitability of pharmacokinetic METHOD for evaluating the bioequivalence of different salbutamol metered dose inhalers (MDIs) by comparing the result with that of the pharmacodynamic method.METHODS A two treatment,two period,randomized,crossover design was adopted.Single dose of 400 μg salbutamol was given to patients with mild to moderate asthma.The blood samples were collected at 0,5,10,15,20 and 30 min after administration.The plasma concentrations of salbutamol were determined by HPLC.Two one sided t-tests and 90% confidence interval were used to evaluate the bioequivalence between the two products.The parameters of pulmonary function,FEV_1.0,PEF,FVC,FEF_25～75,and the safety parameter,heart rate (HR),were measured up to 6 h respectively.For all these parameters,comparisons were made by paired t test.And those parameters with significant difference were selected for ANOVA.RESULTS The bioavailability parameters were obtained as following:c_max(1.22±0.73) and (0.98±0.52 ) ng·mL^-1,t_max (0.21±0.09) and (0.26±0.08) h,AUC_0～20 min (0.25±0.10) and (0.18±0.10) ng·h·mL^-1,respectively.The relative bioavailability of the generic product was 63%.Two one sided t-tests and 90% CI (45%～88%) demonstrated that the two salbutamol MDIs were not bioequivalent.Ventolin produced stronger bronchodilating effect than the generic product.ANOVA on the key pharmacodynamic parameters showed that the two salbutamol MDIs were not equivalent.CONCLUSION S The bioequivalence evaluation result obtained from the pharmacokinetic method was in conformity with that from pharmacodynamic method,indicating that pharmacokinetic method was suitable for evaluating the bioequivalence of salbutamol MDIs.