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

Abstract

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.

FIG 1

Observed micafungin concentrations in plasma (black symbols) and tissue fluid (red symbols). Posterior predictions of the concentration-time curve for plasma (black) and tissue fluid (red) are denoted with solid lines (n = 25 patients).

FIG 2

Structural pharmacokinetic model for micafungin in critically ill patients with intraperitoneal drains in situ. The model was linear and contained volume compartments for the central compartment (plasma; V_central), the peritoneal fluid compartment, and the peripheral compartment. Abbreviations: IV, intravenous; k_cp, rate constant for the drug distribution from the central to the peripheral compartment; k_pc, rate constant for the drug distribution from the peripheral to the central compartment; V_central, volume of distribution of the central compartment; k_ct, rate constant for the drug distribution from the central to the tissue fluid compartment; k_tc, rate constant for the drug distribution from the tissue fluid to the central compartment; CL, clearance.

FIG 3

Diagnostic plots for the final covariate model. (Top) Observed versus population predicted concentrations and individual predicted concentrations in plasma; (bottom) observed versus population predicted concentrations and individual predicted concentrations in tissue fluid. Red points, data for patients with intra-abdominal infections; black points, data for burn patients.

FIG 4

Visual predictive check (n = 1,000 simulations) of plasma data (a) and tissue data (b) from the final covariate model showing that the population pharmacokinetic model has adequate performance; the raw data for individual patients are shown as dots, and the continuous lines represent the 5th, 25th, 50th, 75th, and 95th percentiles of the simulations.