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Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis.

Gonzalez JM, Rodriguez CA, Zuluaga AF, Agudelo M, Vesga O - PLoS ONE (2015)

Bottom Line: Some generics of antibacterials fail therapeutic equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals.The Hill's model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis.In conclusion, the generic products studied were pharmaceutically and therapeutically equivalent to the innovator of fluconazole.

View Article: PubMed Central - PubMed

Affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Universidad de Antioquia, Medellín, Colombia.

ABSTRACT
Some generics of antibacterials fail therapeutic equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals. We used the neutropenic mice model of disseminated candidiasis to challenge the therapeutic equivalence of three generic products of fluconazole compared with the innovator in terms of concentration of the active pharmaceutical ingredient, analytical chemistry (liquid chromatography/mass spectrometry), in vitro susceptibility testing, single-dose serum pharmacokinetics in infected mice, and in vivo pharmacodynamics. Neutropenic, five week-old, murine pathogen free male mice of the strain Udea:ICR(CD-2) were injected in the tail vein with Candida albicans GRP-0144 (MIC = 0.25 mg/L) or Candida albicans CIB-19177 (MIC = 4 mg/L). Subcutaneous therapy with fluconazole (generics or innovator) and sterile saline (untreated controls) started 2 h after infection and ended 24 h later, with doses ranging from no effect to maximal effect (1 to 128 mg/kg per day) divided every 3 or 6 hours. The Hill's model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis. All products were identical in terms of concentration, chromatographic and spectrographic profiles, MICs, mouse pharmacokinetics, and in vivo pharmacodynamic parameters. In conclusion, the generic products studied were pharmaceutically and therapeutically equivalent to the innovator of fluconazole.

No MeSH data available.


Related in: MedlinePlus

Pharmacodynamics of FLC generic products compared with the innovator against C. albicans CIB-19177.Data from two independent experiments were combined and analyzed by CFA. The innovator (Diflucan) was included in both experiments (42 animals), and Claris, Fresenius and Vitalis in one (21 animals per product). A single curve (solid black line) described the data better than individual ones, indicating that the generics were therapeutically equivalent to the innovator. The horizontal dotted line indicates the fungal load at the beginning of therapy (0 h).
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pone.0141872.g002: Pharmacodynamics of FLC generic products compared with the innovator against C. albicans CIB-19177.Data from two independent experiments were combined and analyzed by CFA. The innovator (Diflucan) was included in both experiments (42 animals), and Claris, Fresenius and Vitalis in one (21 animals per product). A single curve (solid black line) described the data better than individual ones, indicating that the generics were therapeutically equivalent to the innovator. The horizontal dotted line indicates the fungal load at the beginning of therapy (0 h).

Mentions: Similar results were found against the less susceptible strain C. albicans CIB-19177. Fig 2 displays the exposure-response curves for the innovator and generic fluconazole products from two different experiments, and Table 5 shows the corresponding pharmacodynamic parameters. Again, the statistical comparison by CFA (P = 0.08) indicated that all data belonged to the same population and was best described by a single curve, confirming the therapeutic equivalence. Against this strain, the fAUC/MIC for ED50 was 25.1±1.03.


Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis.

Gonzalez JM, Rodriguez CA, Zuluaga AF, Agudelo M, Vesga O - PLoS ONE (2015)

Pharmacodynamics of FLC generic products compared with the innovator against C. albicans CIB-19177.Data from two independent experiments were combined and analyzed by CFA. The innovator (Diflucan) was included in both experiments (42 animals), and Claris, Fresenius and Vitalis in one (21 animals per product). A single curve (solid black line) described the data better than individual ones, indicating that the generics were therapeutically equivalent to the innovator. The horizontal dotted line indicates the fungal load at the beginning of therapy (0 h).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4633286&req=5

pone.0141872.g002: Pharmacodynamics of FLC generic products compared with the innovator against C. albicans CIB-19177.Data from two independent experiments were combined and analyzed by CFA. The innovator (Diflucan) was included in both experiments (42 animals), and Claris, Fresenius and Vitalis in one (21 animals per product). A single curve (solid black line) described the data better than individual ones, indicating that the generics were therapeutically equivalent to the innovator. The horizontal dotted line indicates the fungal load at the beginning of therapy (0 h).
Mentions: Similar results were found against the less susceptible strain C. albicans CIB-19177. Fig 2 displays the exposure-response curves for the innovator and generic fluconazole products from two different experiments, and Table 5 shows the corresponding pharmacodynamic parameters. Again, the statistical comparison by CFA (P = 0.08) indicated that all data belonged to the same population and was best described by a single curve, confirming the therapeutic equivalence. Against this strain, the fAUC/MIC for ED50 was 25.1±1.03.

Bottom Line: Some generics of antibacterials fail therapeutic equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals.The Hill's model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis.In conclusion, the generic products studied were pharmaceutically and therapeutically equivalent to the innovator of fluconazole.

View Article: PubMed Central - PubMed

Affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Universidad de Antioquia, Medellín, Colombia.

ABSTRACT
Some generics of antibacterials fail therapeutic equivalence despite being pharmaceutical equivalents of their innovators, but data are scarce with antifungals. We used the neutropenic mice model of disseminated candidiasis to challenge the therapeutic equivalence of three generic products of fluconazole compared with the innovator in terms of concentration of the active pharmaceutical ingredient, analytical chemistry (liquid chromatography/mass spectrometry), in vitro susceptibility testing, single-dose serum pharmacokinetics in infected mice, and in vivo pharmacodynamics. Neutropenic, five week-old, murine pathogen free male mice of the strain Udea:ICR(CD-2) were injected in the tail vein with Candida albicans GRP-0144 (MIC = 0.25 mg/L) or Candida albicans CIB-19177 (MIC = 4 mg/L). Subcutaneous therapy with fluconazole (generics or innovator) and sterile saline (untreated controls) started 2 h after infection and ended 24 h later, with doses ranging from no effect to maximal effect (1 to 128 mg/kg per day) divided every 3 or 6 hours. The Hill's model was fitted to the data by nonlinear regression, and results from each group compared by curve fitting analysis. All products were identical in terms of concentration, chromatographic and spectrographic profiles, MICs, mouse pharmacokinetics, and in vivo pharmacodynamic parameters. In conclusion, the generic products studied were pharmaceutically and therapeutically equivalent to the innovator of fluconazole.

No MeSH data available.


Related in: MedlinePlus