Therapeutic Equivalence Requires Pharmaceutical, Pharmacokinetic, and Pharmacodynamic Identities: True Bioequivalence of a Generic Product of Intravenous Metronidazole
Therapeutic Equivalence Requires Pharmaceutical, Pharmacokinetic, and Pharmacodynamic Identities: True Bioequivalence of a Generic Product of Intravenous Metronidazole
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DOI：
10.1128/aac.06012-11
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发表时间：
2012-05-01
影响因子：
4.9
通讯作者：
Vesga, O.
中科院分区：
文献类型：
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作者：
Agudelo, M.;Vesga, O.
感染的动物模型已被用于证明“生物等效”仿制药的治疗失败，但其适用于这一目的需要准确识别那些真正具有生物等效性的产品。在这里，我们提出的数据比较一个静脉注射甲硝唑仿制药与创新产品在小鼠大腿厌氧菌感染模型。同时进行的实验允许比较（仿制药与原研药）效价和活性药物成分（API）浓度，分析化学（液相色谱/质谱[LC/MS]），体外敏感性试验，感染小鼠单次给药血清药代动力学（PK），以及在贫血小鼠大腿厌氧感染模型中协同大肠杆菌SIG-1对抗脆弱拟杆菌ATCC 25825的体内药效学（PD）。使用Hill剂量-反应模型，然后进行曲线拟合分析，计算并比较主要和次要PD参数。仿制药和原研药在API的浓度和效价、色谱和光谱特征、MIC和最小杀菌浓度（MBC）（2.0 mg/L）以及小鼠PK方面相同。我们发现产品之间在抑菌剂量（BD）（15至22 mg/kg体重/天）或杀死1 log（1 LKD）（21至29 mg/kg/天）或2 log（2LKD）（28至54 mg/kg/天）B所需的剂量方面没有差异。在每12 h（q12 h）、q8 h或q6 h给药方案下，稳态下24 h的浓度-时间曲线下面积除以MIC AUC/MIC比值是预测甲硝唑抗菌效果的最佳PD指标（调整后的决定系数[RR（2）] = 84.6%），两种产品达到体内抑菌作用（56.6 +/- 5.17 h）或杀死第一个对数（90.8 +/- 9.78 h）和第二个对数（155.5 +/- 22.2 h）的量级相同。感染的动物模型允许全面证明通用抗菌药物的治疗等效性。
Animal models of infection have been used to demonstrate the therapeutic failure of "bioequivalent" generic products, but their applicability for this purpose requires the accurate identification of those products that are truly bioequivalent. Here, we present data comparing one intravenous generic product of metronidazole with the innovator product in a neutropenic mouse thigh anaerobic infection model. Simultaneous experiments allowed comparisons (generic versus innovator) of potency and the concentration of the active pharmaceutical ingredient (API), analytical chemistry (liquid chromatography/mass spectrometry [LC/MS]), in vitro susceptibility testing, single-dose serum pharmacokinetics (PK) in infected mice, and in vivo pharmacodynamics (PD) against Bacteroides fragilis ATCC 25825 in synergy with Escherichia coli SIG-1 in the neutropenic mouse thigh anaerobic infection model. The Hill dose-response model followed by curve-fitting analysis was used to calculate and compare primary and secondary PD parameters. The generic and the innovator products were identical in terms of the concentration and potency of the API, chromatographic and spectrographic profiles, MIC and minimal bactericidal concentrations (MBC) (2.0 mg/liter), and mouse PK. We found no differences between products in bacteriostatic doses (BD) (15 to 22 mg/kg of body weight per day) or the doses needed to kill 1 log (1LKD) (21 to 29 mg/kg per day) or 2 logs (2LKD) (28 to 54 mg/kg per day) of B. fragilis under dosing schedules of every 12 h (q12h), q8h, or q6h. The area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) was the best PD index to predict the antibacterial efficacy of metronidazole (adjusted coefficient of determination [AdjR(2)] = 84.6%), and its magnitude to reach bacteriostasis in vivo (56.6 +/- 5.17 h) or to kill the first (90.8 +/- 9.78 h) and second (155.5 +/- 22.2 h) logs was the same for both products. Animal models of infection allow a thorough demonstration of the therapeutic equivalence of generic antimicrobials.