盐酸二甲双胍肠溶片上市后人体生物等效性再评价

 目的 对已上市的盐酸二甲双胍肠溶片的人体生物等效性进行再评价。方法 采用转篮法和紫外分光光度法考察4个厂家（A、B、C、D）的盐酸二甲双胍肠溶片的体外释放度,选择其中2个厂家的盐酸二甲双胍肠溶片作为受试制剂（受试制剂1和受试制剂2）,以原研药盐酸二甲双胍片（格华止）为参比制剂。21名健康男性受试者随机分组,于3个周期交叉服用受试制剂1、受试制剂2和参比制剂500 mg,采用LC-MS/MS测定血浆样本中二甲双胍的浓度,计算药动学参数及2种受试制剂相对于参比制剂的平均相对生物利用度,采用（1-2α）置信区间法评价2种受试制剂与参比制剂的生物等效性,以及2种受试制剂之间的生物等效性。结果 除A厂家的盐酸二甲双胍肠溶片在酸中释放度不符合2010年版《中国药典》增补本拟新增品种公示中的规定外,其他3个厂家的产品均符合规定,且4个厂家的盐酸二甲双胍肠溶片在缓冲液中释放度均符合规定。选择A和D厂家的盐酸二甲双胍肠溶片作为受试制剂1和受试制剂2。受试制剂1的平均相对生物利用度F_0-t和F0-∞分别为（72.8±9.7）%、（73.2±10.0）%,受试制剂2的平均相对生物利用度F0-t和F0-∞分别为（45.5±16.2）%、（46.2±16.0）%。受试制剂1、受试制剂2和参比制剂的ρ_max、AUC_0-t和AUC_0-∞分别经对数转换后进行（1-2α）置信区间检验,不能判定受试制剂1与参比制剂不具有生物等效性,受试制剂2与参比制剂不具有生物等效性,2种受试制剂之间也不具有生物等效性。 结论 盐酸二甲双胍肠溶片为生物不等效风险高的品种,建议不仅应在上市前选择合适的参比制剂进行规范的生物等效性研究,更应加强其上市后的生物等效性监测与再评价,确保不同厂家、同一厂家不同批次的药品质量的一致性。

Post-Marketing Reevaluation of Bioequivalence of Metformin Hydrochloride Enteric-Coated Tablets

OBJECTIVE To reevaluate the bioequivalence of marked metformin hydrochloride enteric-coated tablets.METHODSUsing method 2 described in the appendix X D and apparatus 1 described in the appendix X C in Chinese Pharmacopoeia（edition 2010）,the in vitro release of metformin hydrochloride enteric-coated tablets from different pharmaceutical factories （A,B,C,and D） was investigated. The contents were measured by utlraviolet （UV）spectroscopy.Generic tablets from factory A and D were chosen to be test 1 and test 2 preparations,with the innovative metformin hydrochloride tablets （Glucophage） as the reference preparation. In a randomized,three-way crossover study,21 healthy male volunteers were given a single oral dose of test 1,test 2 and reference preparations containing 500 mg of metformin hydrochloride. Plasma concentrations of metformin were determined by LC-MS/MS. The pharmacokinetic parameters and relative bioavailability were calculated. The bioequivalence between test 1 and reference preparation,test 2 and reference preparation,and the bioequivalence between the two test preparations were evaluated.RESULTS The in vitro release of metformin hydrochloride enteric-coated tablets from factory B,C and D met the standard of Chinese Pharmacopoeia（the supplement edition of 2010） while that of the tablets from factory A did not.Metformin hydrochloride enteric-coated tablets from factory A and D were chosen to be test 1 and test 2 preparations,respectively. The F0-t and F0-∞ were （72.8±9.7） % and （73.2±10.0） % for test 1 preparation,and （45.5±16.2） % and （46.2±16.0） % for test 2 preparation,respectively. It was failed to conclude that test 1 and reference preparation were bioinequivalent. Test 2 and reference preparation were bioinequivalent,and the two test preparations were also bioinequivalent.CONCLUSION The bioinequivalence risk of metformin hydrochloride enteric-coated tablets is high. For metformin hydrochloride enteric-coated tablets,not only conducting pre-marketing bioequivalence study with proper reference preparation,but also enhancing post-marketing surveillance and reevaluation of bioequivalence are very important for maintaining the consistency of drugs quality．