Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation.
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.



One hundred patients were included and 436 concentrations were available for PK analysis performed with NONMEM software. PTA was determined by Monte Carlo simulations.



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.



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.
Pharmacology Department, Georges Pompidou Hospital, Paris Descartes University, Paris, France vincent.jullien@aphp.fr.
Vincent
V
Jullien
Saint-Louis University Hospital, Medical ICU, Paris, France.
Elie
E
Azoulay
Medical ICU, Albert Michallon University Hospital, Grenoble, France.
Carole
C
Schwebel
Pharmacology Department, Georges Pompidou Hospital, Paris Descartes University, Paris, France.
Thomas
T
Le Saux
Medical ICU, François Mitterand University Hospital, Dijon, France.
Pierre Emmanuel
PE
Charles
UMR5525 CNRS-Grenoble Alpes University, Parasitology-Mycology, Grenoble Alpes University Hospital, Grenoble, France.
Muriel
M
Cornet
Medical ICU, Gabriel Montpied University Hospital, Clermont-Ferrand, France.
Bertrand
B
Souweine
Medical ICU, Lapeyronie University Hospital, Montpellier, France.
Kadda
K
Klouche
Department of Critical Care Medicine and Anesthesiology (DAR B) Saint Eloi University, Hospital and Montpellier School of Medicine University of Montpellier, INSERM U1046, CNRS UMR 9214, Montpellier, France.
Samir
S
Jaber
Medical ICU, Institut de Cardiologie, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Jean-Louis
JL
Trouillet
Medical ICU, André Mignot Hospital, Versailles, France.
Fabrice
F
Bruneel
Medical ICU, Edouard Herriot University Hospital, Lyon, France.
Martin
M
Cour
Medical Surgical ICU, CHU Reims, Reims, France.
Joel
J
Cousson
Service de Réanimation Médicale, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Ferhat
F
Meziani
Medical ICU, Bordeaux University Hospital, Bordeaux, France.
Didier
D
Gruson
Clinical Research and Innovation Direction, Grenoble Alpes University Hospital, Grenoble F-38043, France.
Adeline
A
Paris
Medical ICU, Saint-Etienne University Hospital, Saint-Priest en Jarez, France.
Michael
M
Darmon
Medical-Surgical ICU, Saint-Joseph Hospital Network, Paris, France.
Maité
M
Garrouste-Orgeas
Surgical ICU, CHU Jean Minjoz, Besancon, France.
Jean-Christophe
JC
Navellou
Surgical ICU, APHP, CHU Beaujon, Clichy, France.
Arnaud
A
Foucrier
Surgical ICU, Hospices Civils de Lyon, Hopital Sud, Lyon, France.
Bernard
B
Allaouchiche
Polyvalent ICU, CH de Montreuil, Montreuil, France.
Vincent
V
Das
Mycology Laboratory, Rennes University Hospital, Rennes, France.
Jean-Pierre
JP
Gangneux
ICUREsearch, Department of Biostatistics, Paris, France.
Stéphane
S
Ruckly
UMR1137-IAME Inserm, Paris Diderot University, Paris, France.|Medical and Infectious Diseases ICU, Bichat-Claude Bernard University Hospital, Paris, France.
Michel
M
Wolff
UMR1137-IAME Inserm, Paris Diderot University, Paris, France.|Medical and Infectious Diseases ICU, Bichat-Claude Bernard University Hospital, Paris, France.
Jean-François
JF
Timsit
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D058387:Candidemia / Q000188:drug therapy*; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D055666:Lipopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D000077551:Micafungin; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D012121:Respiration, Artificial
D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D000077551:Micafungin