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      About the Validation of Animal Models to Study the Pharmacodynamics of Generic Antimicrobials

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      Clinical Infectious Diseases

      Oxford University Press (OUP)

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          Most cited references 13

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          Generic vancomycin products fail in vivo despite being pharmaceutical equivalents of the innovator.

          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.
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            The FDA animal efficacy rule and biodefense.

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              Efficacy and quality of antibacterial generic products approved for human use: a systematic review.

              Concerns have recently emerged about the efficacy and the quality of antibacterial generic products approved for use in humans. We searched Medline and Embase for original research articles on antibacterial generic products published in English or French before July 2013. We selected 37 original research articles: 15 on β-lactams, 10 on glycopeptides, and 12 on other antibacterial agents. The majority of articles (73.0%) were published during 2008-2012. Study designs included analytical chemistry (n = 9), in vitro susceptibility studies (n = 14), animal experiments (n = 6, including 5 using the neutropenic mouse thigh infection model), and clinical studies in humans (n = 15). Of the 37 studies, 14 (37.8%) suggested that some generic products may be inferior to the innovator in terms of purity (n = 2), in vitro activity (n = 3), in vivo efficacy in experimental models (n = 4), clinical efficacy (n = 2), taste (n = 2), or compliance and acceptability in children (n = 1). The majority of in vitro studies (78.6%) found no significant difference between generic products and the innovator. Most (5/6) in vivo studies suggesting a difference between generic products and the innovator were performed in an animal model that is not validated for the evaluation of the efficacy of antibacterial agents. The level of evidence was constantly low in clinical studies. Published data on antibacterial generic products are limited and heterogeneous, thus precluding any attempt to generalize the study results. This systematic review suggests that additional evidence would be needed before considering a revision of the marketing authorization process for antibacterial generic products.
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                Author and article information

                Journal
                Clinical Infectious Diseases
                Clinical Infectious Diseases
                Oxford University Press (OUP)
                1058-4838
                1537-6591
                July 14 2014
                April 29 2014
                : 59
                : 3
                : 459-461
                Article
                10.1093/cid/ciu306
                24785234
                © 2014

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