title: Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients.
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/m2A 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.
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Abdulaziz S
authors.initials: AS
authors.lastname: Alobaid
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Wallis
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Jarrett
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Therese
authors.initials: T
authors.lastname: Starr
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Janine
authors.initials: J
authors.lastname: Stuart
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lassig-Smith
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jenny Lisette Ordóñez
authors.initials: JL
authors.lastname: Mejia
authors.affiliation: Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Therapeutics Research Centre, Basil Hetzel Institute for Translational Health Research, The Queen Elizabeth Hospital, Adelaide, Australia.|School of Pharmacy and Medical Science, University of South Australia, Adelaide, Australia.
authors.forename: Mahipal G
authors.initials: MG
authors.lastname: Sinnollareddy
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Department of Anesthesiology, Critical Care Pain, and Emergency Medicine, Nimes University Hospital, Nimes, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Roger
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.|Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.|Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Lipman
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia j.roberts2@uq.edu.au.|Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.|School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D015992:Body Mass Index; D002175:Candida / Q000187:drug effects* / Q000254:growth & development; D002177:Candidiasis / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D016638:Critical Illness; D004334:Drug Administration Schedule; D005260:Female; D015725:Fluconazole / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007362:Intensive Care Units; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015233:Models, Statistical; D009010:Monte Carlo Method; D009767:Obesity, Morbid / Q000150:complications / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011446:Prospective Studies
chemical_list: D000935:Antifungal Agents; D015725:Fluconazole