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Article Dans Une Revue Antimicrobial Agents and Chemotherapy Année : 2016

Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

Abdulaziz Alobaid
  • Fonction : Auteur
Steven Wallis
  • Fonction : Auteur
Paul Jarrett
  • Fonction : Auteur
Therese Starr
  • Fonction : Auteur
Janine Stuart
  • Fonction : Auteur
Melissa Lassig-Smith
  • Fonction : Auteur
Jenny Lisette Ordóñez Mejia
  • Fonction : Auteur
Michael Roberts
  • Fonction : Auteur
Mahipal Sinnollareddy
  • Fonction : Auteur
Jeffrey Lipman
  • Fonction : Auteur
Jason Roberts


Our objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n = 6) and morbidly obese (n = 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2 A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

Dates et versions

hal-01942229 , version 1 (03-12-2018)



Abdulaziz Alobaid, Steven Wallis, Paul Jarrett, Therese Starr, Janine Stuart, et al.. Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients. Antimicrobial Agents and Chemotherapy, 2016, 60 (11), pp.6550-6557. ⟨10.1128/AAC.01088-16⟩. ⟨hal-01942229⟩
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