Pharmacodynamic evaluation of the activities of six parenteral vancomycin products available in the United States.
A recent report found that generic parenteral vancomycin products may not have in vivo efficacies equivalent to those of the innovator in a neutropenic murine thigh infection model despite having similar in vitro microbiological activities and murine serum pharmacokinetics. We compared the in vitro and in vivo activities of six of the parenteral vancomycin products available in the United States. The in vitro assessments for the potencies of the vancomycin products included MIC/minimal bactericidal concentration (MBC) determinations, quantifying the impact of human and murine serum on the MIC values, and time-kill studies. Also, the potencies of the vancomycin products were quantified with a biological assay, and the human and mouse serum protein binding rates for the vancomycin products were measured. The in vivo studies included dose-ranging experiments with the 6 vancomycin products for three isolates of Staphylococcus aureus in a neutropenic mouse thigh infection model. The pharmacokinetics of the vancomycin products were assessed in infected mice by population pharmacokinetic modeling. No differences were seen across the vancomycin products with regard to any in vitro evaluation. Inhibitory sigmoid maximal bacterial kill (Emax) modeling of the relationship between vancomycin dosage and the killing of the bacteria in mice in vivo yielded similar Emax and EC50 (drug exposure driving one-half Emax) values for bacterial killing. Further, there were no differences in the pharmacokinetic clearances of the 6 vancomycin products from infected mice. There were no important pharmacodynamic differences in the in vitro or in vivo activities among the six vancomycin products evaluated.
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA Arnold.Louie@medicine.ufl.edu.
Arnold
A
Louie
Division of Pharmaceutical Analysis, Office of Testing and Research, Office of Pharmaceutical Science, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Michael T
MT
Boyne
Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA.
Vikram
V
Patel
National Institutes of Health, National Institute for Allergy and Infectious Diseases, Bacteriology and Mycology Branch, Division of Microbiology and Infectious Diseases, Bethesda, Maryland, USA.
Clayton
C
Huntley
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
Weiguo
W
Liu
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
Steven
S
Fikes
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
Stephanie
S
Kurhanewicz
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
Jaime
J
Rodriquez
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
Nichole
N
Robbins
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
David
D
Brown
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
Dodge
D
Baluya
Institute for Therapeutic Innovation, University of Florida College of Medicine, Orlando, Florida, USA.
G L
GL
Drusano
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008815:Mice, Inbred Strains; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects*; D014481:United States; D014640:Vancomycin / Q000493:pharmacokinetics* / Q000494:pharmacology
D001798:Blood Proteins; D014640:Vancomycin