Comparative Population Plasma and Tissue Pharmacokinetics of Micafungin in Critically Ill Patients with Severe Burn Injuries and Patients with Complicated Intra-Abdominal Infection

Abstract

g Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ؎ 0.47 versus 0.15 ؎ 0.06 h ؊1 , respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of <0.008 mg/liter and <0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively.

Are we near to the end of the standard dose of micafungin?

“…These results could correlate with, and also support those that we previously obtained in the first study [ 2 ] published on the pharmacokinetics (PK) of micafungin in plasma and burn eschar tissue in critically ill patients with severe burn injuries, which were compared with the PK of micafungin in patients with intra-abdominal infections [ 3 ]. In our study, 15 burn patients were compared with ten patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin.…”

Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients

“…The probability of target attainment was estimated based on target AUC 0–24 h /MIC ratios of 285 and 3000 for C. parapsilosis and C. non - parapsilosis , respectively. By a single dose of 100 mg, targets were achieved for strains with low MICs of ≤0.008 and ≤0.064, respectively [ 385 ].…”

Clinical Pharmacokinetics and Pharmacodynamics of Micafungin

“…The plasma concentrations of micafungin and covariates influencing the concentration have been investigated in 15 population PK models (see Table 2 for details) [ 38 , 41 , 45 , 47 , 52 , 53 , 55 , 58 – 65 ]. In all cases, the plasma concentration was best described using a two-compartment model; additional compartments were used to explain tissue concentrations in two studies [ 41 , 47 ]. In the majority of the models, weight was incorporated to explain variability in systemic CL, and, in approximately half of the models, weight was also able to explain variability in V d of the central compartment.…”

“…and C. parapsilosis species, with MIC values up to 0.008 and 0.064 mg/L, respectively. A licensed dose of 200 mg was found to be sufficient to achieve the European Committee on Antimicrobial Susceptibility Testing (EUCAST) susceptibility target for C. albicans (0.016 mg/L), but not for C. glabrata (0.03 mg/L) [ 41 ].…”