GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Calle 62 No. 52-59, Lab. 630, SIU, UdeA, Medellín, Colombia.
Antimicrob Agents Chemother. 2010 Aug;54(8):3271-9. doi: 10.1128/AAC.01044-09. Epub 2010 Jun 14.
Generic versions of intravenous antibiotics are not required to demonstrate therapeutic equivalence with the innovator because therapeutic equivalence is assumed from pharmaceutical equivalence. To test such assumptions, we studied three generic versions of vancomycin in simultaneous experiments with the innovator and determined the concentration and potency of the active pharmaceutical ingredient by microbiological assay, single-dose pharmacokinetics in infected mice, antibacterial effect by broth microdilution and time-kill curves (TKC), and pharmacodynamics against two wild-type strains of Staphylococcus aureus by using the neutropenic mouse thigh infection model. The main outcome measure was the comparison of magnitudes and patterns of in vivo efficacy between generic products and the innovator. Except for one product exhibiting slightly greater concentration, vancomycin generics were undistinguishable from the innovator based on concentration and potency, protein binding, in vitro antibacterial effect determined by minimal inhibitory or bactericidal concentrations and TKC, and serum pharmacokinetics. Despite such similarities, all generic products failed in vivo to kill S. aureus, while the innovator displayed the expected bactericidal efficacy: maximum antibacterial effect (Emax) (95% confidence interval [CI]) was 2.04 (1.89 to 2.19), 2.59 (2.21 to 2.98), and 3.48 (2.92 to 4.04) versus 5.65 (5.52 to 5.78) log10 CFU/g for three generics and the innovator product, respectively (P<0.0001, any comparison). Nonlinear regression analysis suggests that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible for in vivo failure. In conclusion, pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin.
静脉用抗生素的仿制药不需要证明与原研药具有治疗等效性，因为从药物等效性可以推导出治疗等效性。为了检验这些假设，我们在同时进行的实验中研究了三种万古霉素仿制药，通过微生物测定、感染小鼠的单剂量药代动力学、肉汤微量稀释法和时间杀菌曲线（TKC）测定活性药物成分的浓度和效力，以及使用中性粒细胞减少症小鼠大腿感染模型测定两种金黄色葡萄球菌野生株的药效学，来比较仿制药与原研药的体内疗效的幅度和模式。主要观察指标是比较仿制药与原研药的体内疗效的幅度和模式。除了一种产品的浓度稍高外，根据浓度和效力、蛋白结合、通过最小抑菌浓度或杀菌浓度和 TKC 以及血清药代动力学来确定的体外抗菌作用，万古霉素仿制药与原研药无法区分。尽管存在这些相似性，但所有仿制药在体内均未能杀死金黄色葡萄球菌，而原研药则显示出预期的杀菌效果：最大抗菌效果（Emax）（95%置信区间[CI]）分别为 2.04（1.89 至 2.19）、2.59（2.21 至 2.98）和 3.48（2.92 至 4.04），而三种仿制药和原研药的万古霉素分别为 5.65（5.52 至 5.78）log10 CFU/g（P<0.0001，任何比较）。非线性回归分析表明，万古霉素仿制药的配方中含有抑制和刺激成分，这些成分会导致体内失败的激动拮抗作用。总之，药物等效性并不意味着万古霉素具有治疗等效性。
