Abstract
We investigated covariates of pharmacokinetics of micafungin in critically ill patients. After application of micafungin, plasma samples were collected. Non-linear mixed effects modelling (NONMEM 7.3) was used to develop the pharmacokinetic model. Using this model, the adequacy of a fixed 100 mg dosing regimen was evaluated in the study cohort. A two-compartment model with linear elimination was found to describe the obtained data. SOFA score was identified as a significant covariate on both clearance and central volume of distribution, respectively. Patients in highly critical condition, represented by a SOFA above 10 showed a 30.8% lower central volume of distribution than the less critically ill patients. For patients with bilirubin levels above 4 mg/dl, clearance was decreased by 21.1%. Renal replacement therapy (RRT) did not influence micafungin clearance or the volumes of distribution. In a posthoc evaluation of the modeled population, 100 mg micafungin was suitable when assessing the PKPD targets (AUC/MIC) for C. albicans and C. glabrata, with insufficient target attainment for C. parapsilosis. Micafungin pharmacokinetics appear not to be influenced by the status of RRT. A dose of 100 mg micafungin is suitable for infections with C. albicans and C. glabrata in critically ill patients.
Highlights
Invasive fungal infections in critically ill patients are a serious threat and a cause of high mortality
The 24-h area under the concentration time curve divided by the minimal inhibitory concentration (AUC/MIC) is the pharmacodynamic parameter that best describes the dose-response relation of this drug[10]
The median length of micafungin therapy was 10,5 days and treatment was continued for as long as treating physicians felt it was adequate. 15 patients died in the intensive care unit (ICU); the other patients were discharged alive
Summary
Invasive fungal infections in critically ill patients are a serious threat and a cause of high mortality. A typical focus of infection in this collective is the intraabdominal space, where Candida peritonitis and candidemia develop after perforation of a hollow viscus[3]. The contemporary treatment of invasive candidiasis and candidemia relies on echinocandines as the primary choice of antifungal agents. This strategy is recommended by several clinical guidelines dealing with invasive fungal infections[6,7,8]. Micafungin was the third echinocandin antifungal agent approved by the European Medicines Agency in 2008 It is licensed for the treatment of all types of invasive candidiasis, esophageal candidiasis and for prophylaxis in patients undergoing stem cell transplantation[9]. An increase in free drug levels during hypoalbuminemia is thought to cause an increased clearance in these patients
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