title: Demonstration of Therapeutic Equivalence of Fluconazole Generic Products in the Neutropenic Mouse Model of Disseminated Candidiasis.
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.
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Universidad de Antioquia, Medellín, Colombia.|Scientific Direction, Clínica Cardio VID, Medellín, Colombia.
authors.forename: Javier M
authors.initials: JM
authors.lastname: Gonzalez
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Universidad de Antioquia, Medellín, Colombia.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Rodriguez
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Universidad de Antioquia, Medellín, Colombia.
authors.forename: Andres F
authors.initials: AF
authors.lastname: Zuluaga
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Universidad de Antioquia, Medellín, Colombia.|Infectious Diseases Unit, Hospital Universitario San Vicente Fundación, Medellín, Colombia.
authors.forename: Maria
authors.initials: M
authors.lastname: Agudelo
authors.affiliation: GRIPE (Grupo Investigador de Problemas en Enfermedades Infecciosas), Universidad de Antioquia, Medellín, Colombia.|Infectious Diseases Unit, Hospital Universitario San Vicente Fundación, Medellín, Colombia.
authors.forename: Omar
authors.initials: O
authors.lastname: Vesga
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002176:Candida albicans / Q000187:drug effects; D002177:Candidiasis / Q000188:drug therapy / Q000662:veterinary; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D016568:Drugs, Generic / Q000493:pharmacokinetics / Q000627:therapeutic use; D015725:Fluconazole / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006207:Half-Life; D013058:Mass Spectrometry; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D012372:ROC Curve; D013810:Therapeutic Equivalency
chemical_list: D000935:Antifungal Agents; D016568:Drugs, Generic; D015725:Fluconazole