Population Pharmacokinetics of Micafungin in critically ill patients - evaluation of a fixed dose regimen
Silke Gastine (1), Magalie Blessou (1), Dagmar Horn (2), Christian Lanckohr (2), Björn Ellger (2), Georg Hempel (1)
(1) Department of Pharmaceutical and Medicinal Chemistry, Clinical Pharmacy, Westfälische Wilhelms-Universität Münster, Germany, (2) Department of Anaesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Münster, Germany
Objectives: For the treatment of invasive fungal infections (IFIs) micafungin is usually applied with a fixed dose of 100 mg for all adult patients. In this study, we investigated the influence of different cofactors on the pharmacokinetics of micafungin in critically ill patients. Particular attention was given to time-varying covariates describing the critical state of the patient and the status of renal replacement therapy (RRT).
Methods: Plasma sample collection was conducted at the intensive care unit of the University Hospital of Münster, Germany. Micafungin was applied as short-time infusion once daily with a fixed 100 mg dose.
Non-linear mixed effects modelling (NONMEM 7.3) was used to develop the pharmacokinetic model. For model evaluation, model diagnostic plots were performed using R in combination with the Xpose package. Covariate testing was performed using the SCM module in PSN 4.6.0.
In addition to the demographics of the patients, a retrospective chart review was conducted for covariates such as: Sequential organ failure assessment-score (SOFA-score), simplified acute physiology-score (SAPS II-score), bilirubin, transaminases, pseudocholinesterase (PCHE), status on extra corporal membrane oxygenation (ECMO), albumin, protein and creatinine clearance. Renal replacement therapy (RRT) was documented with following categories: no RRT, slow extended daily dialysis (SLEDD), continuous veno-venous dialysis (CVVHD). All covariates were collected as time varying covariates.
Results: A two compartment model with linear elimination was found to most adequately describe the obtained data.
The SOFA score representing the patients’ critical status was found as significant covariate on both clearance and central volume of distribution, respectively. Clearance decreased linearly by a factor of 0.024 with the SOFA score. Patients in highly critical condition, represented by a SOFA above 10 showed 30.8% lower V1 than the less critically ill patients. For patients with hepatic insufficiency with bilirubin levels above 4 mg/dl, clearance decreases by 21.1%.
The different status in RRT did neither influence micafungin clearance nor the volumes of distribution, but was correlated with the SOFA score.
Conclusions: Micafungin pharmacokinetics appear not to be influenced by the status of RRT. Highly critical patients are more likely to have higher peak concentrations for micafungin and micafungin clearance decreases for patients with elevated bilirubin levels.