Effect of obesity on the population pharmacokinetics of fluconazole in critically Ill patients

Alobaid, Abdulaziz S., Wallis, Steven C., Jarrett, Paul, Starr, Therese, Stuart, Janine, Lassig-Smith, Melissa, Mejia, Jenny Lisette Ordóñez, Roberts, Michael S., Sinnollareddy, Mahipal G., Roger, Claire, Lipman, Jeffrey and Roberts, Jason A. (2016) Effect of obesity on the population pharmacokinetics of fluconazole in critically Ill patients. Antimicrobial Agents and Chemotherapy, 60 11: 6550-6557. doi:10.1128/AAC.01088-16

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Author Alobaid, Abdulaziz S.
Wallis, Steven C.
Jarrett, Paul
Starr, Therese
Stuart, Janine
Lassig-Smith, Melissa
Mejia, Jenny Lisette Ordóñez
Roberts, Michael S.
Sinnollareddy, Mahipal G.
Roger, Claire
Lipman, Jeffrey
Roberts, Jason A.
Title Effect of obesity on the population pharmacokinetics of fluconazole in critically Ill patients
Journal name Antimicrobial Agents and Chemotherapy   Check publisher's open access policy
ISSN 1098-6596
0066-4804
Publication date 2016-11-01
Sub-type Article (original research)
DOI 10.1128/AAC.01088-16
Open Access Status File (Publisher version)
Volume 60
Issue 11
Start page 6550
End page 6557
Total pages 8
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Collection year 2017
Language eng
Formatted abstract
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.
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