Yonsei Med J.  2020 Apr;61(4):301-309. 10.3349/ymj.2020.61.4.301.

Comparison of In Vivo Pharmacokinetics and Pharmacodynamics of Vancomycin Products Available in Korea

• Kim HK
• Choi SM
• Kang G
• Park KH
• Lee DG
• Park WB
• Rhee SJ
• Lee S
• Jung SI
• Jang HC

• KMID: 2471915
• DOI: http://doi.org/10.3349/ymj.2020.61.4.301

Abstract

PURPOSE
Few studies have been investigated the in vivo efficacy of generic vancomycin products available outside of the United States. In this study, we aimed to compare the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of five generic vancomycin products available in Korea with those of the innovator.
MATERIALS AND METHODS
The in vitro vancomycin purity of each product was examined using high-pressure liquid chromatography. Single-dose PK analyses were performed using neutropenic mice. The in vivo efficacy of vancomycin products was compared with that of the innovator in dose-effect experiments (25 to 400 mg/kg per day) using a thigh-infection model with neutropenic mice.
RESULTS
Generic products had a lower proportion of vancomycin B (range: 90.3-93.8%) and a higher proportion of impurities (range: 6.2-9.7%) than the innovator (94.5% and 5.5%, respectively). In an in vivo single-dose PK study, the maximum concentration (C(max)) values of each generic were lower than that of the innovator, and the geographic mean area under the curve ratios of four generics were significantly lower than that of the innovator (all p<0.1). In the thigh-infection model, the maximum efficacies of generic products reflected in maximal effect (E(max)) values were not significantly different from the innovator. However, the PD profile curves of some generic products differed significantly from that of the innovator in mice injected with a high level of Mu3 (all p≤0.05).
CONCLUSION
Some generic vancomycin products available in Korea showed inferior PK and PD profiles, especially in mice infected with hetero-vancomycin-resistant Staphylococcus aureus.

Keyword

efficacy; innovator; original; generic; Vancomycin

MeSH Terms

Animals
Chromatography, Liquid
In Vitro Techniques
Korea*
Mice
Pharmacokinetics*
Staphylococcus aureus
United States
Vancomycin*
Vancomycin

Figure

• 

  Fig. 1 Representative chromatograms of six vancomycin products using the HPLC method. The main peak just before 15.8 min is vancomycin B. The retention time of the vancomycin peak in the test products was consistent with the USP reference standard. HPLC, high-pressure liquid chromatography; USP, U.S. Pharmacopeia.

• 

  Fig. 2 Dose-response relationship of the innovator and five generic products. Five generic vancomycin products were compared with the innovator in dose-effect experiments (25 to 400 mg/kg per day) using a neutropenic mice thigh-infection model by injecting ATCC 29213 at low (A) and high (B) inocula (~4 and ~8 log10 CFU per thigh) and Mu3 at low (C) and high (D) inocula. Innovator and five generics were analyzed by non-linear regression fitting Hill's sigmoid model. Each data point represents the mean CFU/g of both thighs from a single mouse and three experiments. CFU, colony-forming units; CFA, curve fitting analysis.

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