布洛芬颗粒在中国健康受试者的人体生物等效性研究及对该品种生物等效性试验的分析和建议

Study on bioequivalence of ibuprofen granules in healthy Chinese subjects and analysis and suggestion for the bioequivalence testing of ibuprofen granules

关键词:  布洛芬颗粒  生物等效性试验  液相色谱-串联质谱法

Key words:  Ibuprofen Granules  Bioequivalence test  LC-MS/MS

摘要:

摘要：目的 研究受试制剂浙江康恩贝制药股份有限公司生产的布洛芬颗粒和参比制剂Kaken Pharmaceutical Co. Ltd.生产的Brufen?（20%布洛芬颗粒）在健康成年受试者空腹/餐后条件下口服用药的生物等效性，并系统地对比并汇总分析国内已通过仿制药质量和疗效一致性评价的布洛芬颗粒的生物等效性试验设计和结果，对今后布洛芬颗粒的生物等效性试验设计等提供建议。方法 48位健康受试者随机分入空腹及餐后两组。空腹/餐后组24名受试者在空腹/餐后条件下采用随机、开放、双周期、双交叉、单次给药的试验设计，口服两种布洛芬颗粒。然后采用LC-MS/MS 法测定受试者血浆内布洛芬的浓度。通过WinNonlin 7.0计算药代动力学参数，以评价受试制剂与参比制剂之间的生物等效性。通过对比并汇总分析了国家食品药品监督管理局审评中心（CDE）披露的已通过一致性评价的另外7个厂家的布洛芬颗粒的生物等效性试验设计和结果，估算关键药代动力学参数的个体内变异系数，从试验类型、样本量、参比制剂、食物影响等方面进行分析。结果 本次试验下，空腹组受试制剂与参比制剂的Cmax、AUC0-t及AUC0-∞几何均值比的90%置信区间分别为85.84%~98.57%（Cmax）、97.75%~101.18%（AUC0-t）、97.73%~101.32%（AUC0-∞），餐后组受试制剂与参比制剂的Cmax、AUC0-t及AUC0-∞的几何均值比的90%置信区间分别为91.72%~107.26%（Cmax）、95.70%~100.21%（AUC0-t）、95.76%~100.16%（AUC0-∞），均在80.00~125.00%范围。同时，对比其他企业的布洛芬颗粒生物等效性结果，无论参比制剂还是受试制剂，餐后状态下对布洛芬颗粒的吸收有一定的影响，具体呈现Cmax降低的趋势，平均约降低50%左右，但对其AUC0-t和AUC0-∞影响不明显，约降低10%左右。结论 布洛芬颗粒受试制剂和参比制剂在健康受试者空腹和餐后状态下具有生物等效性。本文对布洛芬颗粒的生物等效性试验的分析和建议为今后的布洛芬颗粒的生物等效性研究提供了参考。

Abstract:

To study the bioequivalence of ibuprofen granules produced by Zhejiang CONBA Pharmaceutical Co.Ltd. and Brufen?（20% ibuprofen granules）produced by Kaken Pharmaceutical Co. Ltd. under fasting/fed conditions in healthy adult volunteers. Compare and summarize the design and results of bioequivalence tests for ibuprofen granules that have passed the consistency evaluation of quality and efficacy in domestic generic drugs, and provide suggestions for the design of future bioequivalence tests for ibuprofen granules. METHODS Forty-eight healthy subjects were randomly divided into fasting and fed groups.Twenty-four subjects in the fasting/fed group were given two ibuprofen granules orally in a randomized, open, double-cycle, double-crossover, single-dose trial design under fasting/fed conditions.Then the plasma concentration of ibuprofen was determined by LC-MS/MS. The pharmacokinetic parameters were calculated by WinNonlin 7.0 to evaluate the bioequivalence between the test preparation and the reference preparationt. Conduct a comparative analysis and summary of the bioequivalence test design and results for ibuprofen granules from seven additional manufacturers that have been approved through consistency evaluation by the Center for Drug Evaluation（CDE）of the National Food and Drug Administration（NMPA）, estimate the coefficient of variation in key pharmacokinetic parameters within individuals, and analyze from aspects such as test type, sample size, reference preparation, and food impact.RESULTS In the fasting group, the 90% confidence intervals of the geometric mean ratio of Cmax、AUC0-t and AUC0-∞ were 85.54% to 98.57% (Cmax), 97.75% to 101.18% (AUC0-t), and 97.73% to 101.32% (AUC0-∞) for the test preparations and reference preparations. In the fed group, the 90% confidence intervals of the geometric mean ratio of Cmax、AUC0-t and AUC0-∞ were 91.72% to 107.26% (Cmax), 95.70% to 100.21% (AUC0-t), and 95.76% to 100.16% (AUC0-∞) for the test preparations and reference preparations.The corresponding values were also within the range of 80.00% to 125.00%. Meanwhile, in comparison to bioequivalence results for other companies" ibuprofen granules , both the reference and test formulations are affected by fed conditions, indicating a decrease in Cmax levels after fed. Specifically, there is a trend of decreased Cmax levels, which on average decreases by about 50%,while the impact on AUC0-t and AUC0-∞ is not significant, decreasing by about 10%.CONCLUSION The method of determining the concentration of ibuprofen in human plasma using LC-MS/MS is reliable, and the test formulation is bioequivalent to the reference formulation. The test formulation and reference preparation of ibuprofen granules were found to be bioequivalent in healthy subjects under fasting and fed conditions. The analysis and recommendations for the bioequivalence testing of ibuprofen granules provided in this article serve as a reference for future bioequivalence studies of ibuprofen granules.