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

Abstract

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.

Fractal Geometry and the Pharmacometrics of Micafungin in Overweight, Obese, and Extremely Obese People

“…This is not a surprise, given the BMI categories we examined (1), in which the proportions of overweight and obese people mirror those of the American public. The population pharmacokinetic parameter estimates for our "healthy" volunteers were virtually identical to those determined for patients with fungal infections in studies published in the past (2,9,11,26), which suggests that our findings likely have relevance even for patients with fungemia.…”

“…Micafungin concentrations were modeled using the ADAPT 5 program of D'Argenio and colleagues (5). Based on prior work, micafungin is known to follow two-compartment model pharmacokinetics in humans (2,9,12). Therefore, a two-compartment model with first-order input and elimination was utilized.…”

“…The efficacy of micafungin is linked to the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC 0-24 / MIC ratio) (2,3,8). The AUC is inversely proportional to SCL; thus, as SCL increases, AUC 0-24 /MIC declines, which should affect drug efficacy in a negative fashion.…”

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients

“…The success of therapy in our cohort might be driven by pathogens with low MICs (Ͻ0.03 mg/liter), which would result in 100% target attainment. However, data on susceptibility are lacking in this research, and conclusions on the exposure response in relation to the susceptibility of the pathogen as drawn by Andes et al (40) cannot be substantiated.…”

“…Recently, Andes et al (40) demonstrated by analysis of two micafungin phase III trials that the probability of mycological cure in adult patients with invasive candidiasis or candidemia receiving micafungin therapy (55% were admitted to the ICU) was higher if the patient attained an AUC/MIC ratio between 3,000 and 12,000 compared to a ratio of Ͻ3,000 (98.0% versus 85.1%, respectively). The authors concluded that if the MIC was Ͻ0.06 mg/liter, the vast majority of the patients would attain the lower target of 3,000 (11,12,40). A subgroup analysis of the 55% ICU patients in this cohort is lacking in this paper.…”