Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study

Abstract

This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC_0-24h) divided by the MIC (AUC_0-24h/MIC) of 250, 450, and 865 and maximal concentration (C_max) divided by the MIC (C_max/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V₁ = 9.0 ± 1.2 liters and V₂ = 11.9 ± 2.9 liters. Observed and simulated CAS AUC_0-24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and C_max/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.).

Keywords: PK/PD; caspofungin; intensive care unit; invasive candidiasis; pharmacokinetics.

FIG 1

Observed caspofungin (CAS) plasma concentration-time curve in 13 patients receiving the 140-mg loading dose of caspofungin. Gray solid line, observed individual CAS concentration; black solid line, median of the observed individual CAS concentration; red dashed lines, 5th and 95^th percentiles of simulated individual CAS concentrations; blue dashed line, median of the simulated individual CAS concentration.

FIG 2

Pharmacokinetic-pharmacodynamic target achievement for caspofungin, considering all Candida strains. (A) Probability of target attainment (PTA) for various thresholds of the area under the curve over the MIC (AUC/MIC) ratio. (B) PTA for various thresholds of maximal concentration over MIC (C_max/MIC).