Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia

Antimicrob Agents Chemother. 2011 May;55(5):2113-21. doi: 10.1128/AAC.01430-10. Epub 2011 Feb 7.

Abstract

Echinocandins have become a first-line therapy for invasive candidiasis (IC). Using phase 3 trial data for patients with IC, pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy for micafungin were examined. Micafungin exposures were estimated using a population pharmacokinetic model, and univariable and multivariable logistic regressions were used to identify factors associated with outcome, including the micafungin area under the concentration-time curve (AUC)/MIC ratio. Monte Carlo simulation was used to evaluate the probability of achieving AUC/MIC ratios associated with efficacy. Mycological and clinical success rates for evaluable cases were 89.4 and 90.9, respectively. MIC50s and MIC90s for Candida species inhibition were 0.008 and 0.5 mg/liter, respectively. The median AUC/MIC ratio was 15,511 (range, 41.28 to 98,716). Univariable analyses revealed a significant relationship between the AUC/MIC ratio and mycological response, with the worst response being among patients with lower (≤3,000) AUC/MIC ratios (P=0.005). For patients with Candida parapsilosis, AUC/MIC ratios of ≥285 were predictive of a higher mycological response (P=0.11). Multivariable logistic regression demonstrated the AUC/MIC ratio, APACHE II score, and history of corticosteroid use to be significant independent predictors of a favorable response. PK-PD target attainment analyses suggested that 76.7% and 100% of patients would achieve an AUC/MIC ratio of ≥3,000 for an MIC of 0.03 mg/liter and an AUC/MIC ratio of ≥285 for an MIC of <0.5 mg/liter, respectively. The identification of a lower AUC/MIC ratio target for C. parapsilosis than other Candida species suggests consideration of species-specific echinocandin susceptibility breakpoints and values that are lower than those currently approved by regulatory agencies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / pharmacokinetics*
  • Antifungal Agents / therapeutic use
  • Candidemia / blood
  • Candidemia / drug therapy*
  • Candidiasis / blood
  • Candidiasis / drug therapy*
  • Clinical Trials, Phase III as Topic
  • Echinocandins / pharmacokinetics*
  • Echinocandins / therapeutic use
  • Female
  • Humans
  • Lipopeptides / pharmacokinetics*
  • Lipopeptides / therapeutic use
  • Male
  • Micafungin
  • Microbial Sensitivity Tests
  • Middle Aged
  • Monte Carlo Method
  • Randomized Controlled Trials as Topic

Substances

  • Antifungal Agents
  • Echinocandins
  • Lipopeptides
  • Micafungin