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Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation
Vincent Jullien1, Elie Azoulay2, Carole Schwebel3
1Pharmacology Department, Georges Pompidou Hospital, Paris Descartes University, Paris, France vincent.jullien@aphp.fr.
Objectives:
To identify the factors associated with the interindividual pharmacokinetic (PK) variability of micafungin and to evaluate the probability of reaching the previously determined PK/pharmacodynamic efficacy thresholds (AUC/MIC >5000 for non-parapsilosis Candida sp. and ≥285 for Candida parapsilosis) with the recommended 100 mg daily dose in ICU patients with sepsis and mechanical ventilation.
Methods:
One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations.
Results:
Micafungin obeyed a two-compartment model with first-order elimination from the central compartment. Mean parameter estimates (percentage interindividual variability) were 1.34 L/h (34%) for clearance (CL), 11.80 L (38%) and 7.68 L (39%) for central (Vc) and peripheral (Vp) distribution volumes, respectively, and 4.67 L/h (37%) for distribution clearance. CL, Vc and Vp increased by 14% when the albumin level was ≤25 g/L and CL decreased by 25% when SOFA score was ≥10. Body weight was related to CL, Vc and Vp by allometric models. PTA was ≥90% in Candida albicans and Candida glabrata infections, except when the MIC was ≥0.015 mg/L, and ranged between 0% and 40% for C. parapsilosis infections with MIC ≥0.5 mg/L.
Conclusions:
A possible increase in the dose should be evaluated for infections due to C. parapsilosis and for infections due to C. albicans and C. glabrata with MICs ≥0.015 mg/L.
Insights
Micafungin dosing in ICU patients requires adjustment for low albumin or high SOFA scores. Probability of reaching efficacy targets is low for Candida parapsilosis infections, suggesting dose increases may be needed.
Area of Science:
- Pharmacokinetics and Pharmacodynamics
- Infectious Diseases
- Critical Care Medicine
Background:
- Micafungin is an echinocandin antifungal used for invasive Candida infections.
- Interindividual variability in micafungin pharmacokinetics (PK) can affect treatment efficacy.
- Optimizing micafungin dosing in critically ill patients is crucial for achieving therapeutic goals.
Purpose of the Study:
- To identify factors influencing micafungin PK variability in ICU patients with sepsis and mechanical ventilation.
- To assess the probability of achieving target micafungin exposure (AUC/MIC) with standard dosing.
- To guide potential dose adjustments for specific patient populations and Candida species.
Main Methods:
- Population PK analysis using NONMEM software with 436 micafungin concentrations from 100 patients.
- Probability of Target Attainment (PTA) calculated via Monte Carlo simulations.
- Factors evaluated included albumin levels, SOFA score, and body weight.
Main Results:
- Micafungin PK followed a two-compartment model with significant interindividual variability in clearance and distribution volumes.
- Lower albumin levels (≤25 g/L) increased clearance, while higher SOFA scores (≥10) decreased it.
- PTA was high for Candida albicans and glabrata unless MICs were elevated; PTA was low for Candida parapsilosis with MICs ≥0.5 mg/L.
Conclusions:
- Micafungin dosing may need adjustment based on albumin levels and SOFA scores in ICU patients.
- Current dosing regimens may be insufficient for Candida parapsilosis infections, especially with higher MICs.
- Consideration of increased micafungin dosage is warranted for specific challenging infections to improve outcomes.
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