In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model

Antimicrob Agents Chemother. 2003 Oct;47(10):3165-9. doi: 10.1128/AAC.47.10.3165-3169.2003.

Abstract

In vivo studies have described the pharmacodynamic (PD) characteristics of several triazoles. These investigations have demonstrated that the 24-h area under the concentration-time curve (AUC)/MIC ratio is the critical pharmacokinetic (PK)-PD parameter associated with treatment efficacy. Further analyses from these in vivo studies have demonstrated that a triazole free drug 24-h AUC/MIC of 20 to 25 is predictive of treatment success. We used a neutropenic murine model of disseminated Candida albicans infection to similarly characterize the PK-PD of the new triazole voriconazole. PK and PD parameters (percentage of time that the concentration remains above the MIC [T > MIC], AUC/MIC ratio, and peak level in serum/MIC ratio) were correlated with in vivo efficacy, as measured by the organism number in kidney cultures after 24 h of therapy. Voriconazole kinetics and protein binding were studied in infected neutropenic mice. Peak level/dose and AUC/dose values ranged from 0.1 to 0.2 and 0.1 to 0.7, respectively. The serum elimination half-life ranged from 0.7 to 2.9 h. The level of protein binding in mouse serum was 78%. Treatment efficacy with the four dosing intervals studied was similar, supporting the AUC/MIC ratio as the PK-PD parameter predictive of efficacy. Nonlinear regression analysis also suggested that the AUC/MIC ratio was strongly predictive of treatment outcomes (R(2) for AUC/MIC ratio = 82%, R(2) for peak level/MIC ratio = 63%, R(2) for T > MIC = 75%). Similar studies were conducted with nine additional C. albicans isolates with various voriconazole susceptibilities (MICs, 0.007 to 0.25 micro g/ml) to determine if a similar 24-h AUC/MIC ratio was associated with efficacy. The voriconazole free drug AUC/MIC ratios were similar for all of the organisms studied (range, 11 to 58; mean +/- standard deviation, 24 +/- 17 [P = 0.45]). These AUC/MIC ratios observed for free drug are similar to those observed for other triazoles in this model.

MeSH terms

  • Administration, Oral
  • Animals
  • Antifungal Agents / pharmacokinetics*
  • Antifungal Agents / pharmacology*
  • Area Under Curve
  • Candida albicans / drug effects
  • Candida albicans / genetics
  • Candida albicans / growth & development
  • Candida albicans / isolation & purification
  • Candidiasis / blood
  • Candidiasis / drug therapy*
  • Candidiasis / metabolism*
  • Colony Count, Microbial
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Resistance, Fungal
  • Female
  • Fluconazole / pharmacology
  • Kidney / metabolism
  • Mice
  • Microbial Sensitivity Tests
  • Neutropenia / metabolism
  • Pyrimidines / blood
  • Pyrimidines / pharmacokinetics*
  • Pyrimidines / pharmacology*
  • Triazoles / blood
  • Triazoles / pharmacokinetics*
  • Triazoles / pharmacology*
  • Voriconazole

Substances

  • Antifungal Agents
  • Pyrimidines
  • Triazoles
  • Fluconazole
  • Voriconazole