Use of Pharmacokinetic-Pharmacodynamic Analyses To Optimize Therapy with the Systemic Antifungal Micafungin for Invasive Candidiasis or Candidemia

作者：Andes David^*; Ambrose Paul G; Hammel Jeffrey P; Van Wart Scott A; Iyer Varsha; Reynolds Daniel K; Buell Donald N; Kovanda Laura L; Bhavnani Sujata M

来源：Antimicrobial Agents and Chemotherapy, 2011, 55(5): 2113-2121.

DOI：10.1128/AAC.01430-10

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. MIC(50)s and MIC(90)s 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.

• 出版日期2011-5