微生物测定法在非专利静脉注射抗生素药物等效性测定中的应用。

Andres F Zuluaga, Maria Agudelo, Carlos A Rodriguez, Omar Vesga
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引用次数: 99

摘要

背景:证明仿制药和创新药之间相同活性药物成分(API)的等效量(药物等效性)是监管机构对静脉注射仿制药临床使用前的基本要求,也是假设治疗等效的关键。在测定生物液体中的药物浓度时,首选物理化学方法而不是生物测定法,但它不允许直接定量效力。在这里,我们报告了一种微生物测定方法,使用设计的大板来确定注射用药用级抗生素的效价和浓度,并使用统计方法来评估仿制产品相对于创新产品的体外等效性。方法:在Difco抗生素培养基中,测定抗生素对参比菌(枯草芽孢杆菌ATCC 6633、金黄色葡萄球菌ATCC 6538p和表皮葡萄球菌ATCC 12228)抑制效果的浓度依赖性变化,建立y轴截距(浓度)和斜率(效价)的浓度-响应线性关系。采用Graphpad Prism 5.0对22种仿制药(阿米卡星4、庆大霉素15、万古霉素3)的参数与创新药和参比粉进行综合归线符合性检验。结果:验证方法具有良好的线性度(r(2) >或= 0.98)、精密度(测定内变异<或= 11%;测定间变异<或= 10%)、准确性和特异性试验符合国际药典要求。除1个万古霉素仿制药API值高出25% (P(y截距)= 0.001)外,其余21个仿制药的斜率和截距均无差异(P > 0.66)。阿米卡星、庆大霉素和万古霉素仿制药的效价估计分别为99.8% ~ 100.5%、99.7% ~ 100.2%和98.5 ~ 99.9%。结论:该方法可快速、节约成本、精确、准确地测定药物剂型中的药物等效性,可作为仿制抗生素批准人用前的检测技术。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics.

Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics.

Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics.

Application of microbiological assay to determine pharmaceutical equivalence of generic intravenous antibiotics.

Background: Demonstration of equivalent amounts of the same active pharmaceutical ingredient (API) between generic and innovator products (pharmaceutical equivalence) is a basic requirement of regulatory agencies for intravenous generic drugs prior to clinical use, and constitutes the pivotal point to assume therapeutic equivalence. Physicochemical methods are preferred instead of biological assays to determine concentration of drugs in biological fluids, but it does not permit direct quantification of potency. Here, we report a microbiological assay using large plates designed to determine potency and concentration of pharmaceutical-grade antibiotics for injection and a statistical method to assess the in vitro equivalence of generic products with respect to the innovator.

Methods: The assay is based on the concentration-dependent variation of the inhibitory effect of antibiotics on reference bacteria (B. subtilis ATCC 6633, S. aureus ATCC 6538p and S. epidermidis ATCC 12228) in a seeded agar (Difco Antibiotic Media), producing a concentration-response linear relationship with two parameters: y-intercept (concentration) and slope (potency). We compared the parameters of 22 generic products (amikacin 4, gentamicin 15, and vancomycin 3 products) against the innovator and the reference powder by Overall Test for Coincidence of the Regression Lines (Graphpad Prism 5.0).

Results: The validation method yielded excellent results for linearity (r(2) > or = 0.98), precision (intra-assay variation < or = 11%; inter-assay variation < or = 10%), accuracy, and specificity tests according to international pharmacopoeial requirements. Except for one generic of vancomycin that had 25% more API (P(y-intercept) = 0.001), the pharmaceutical equivalence was demonstrated in 21 generics with undistinguishable slopes and intercepts (P > 0.66). Potency estimates were 99.8 to 100.5, 99.7 to 100.2 and 98.5 to 99.9% for generic products of amikacin, gentamicin and vancomycin, respectively.

Conclusion: The proposed method allows rapid, cost-saving, precise, and accurate determination of pharmaceutical equivalence of drugs in pharmaceutical dosage-form, and may be used as a technique for testing generic antibiotics prior to their approval for human use.

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