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

Abdulaziz S. Alobaid, Steven C. Wallis, Paul Jarrett, Therese Starr, Janine Stuart, Melissa Lassig-Smith, Jenny Lisette Ordóñez Mejia, Michael S. Roberts, Mahipal G. Sinnollareddy, Claire Roger, Jeffrey Lipman, Jason A. Roberts

To describe the population pharmacokinetics of fluconazole in a cohort of critically ill non-obese, obese and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, non-obese (18.5-29.9 kg/m(2)); obese (30.0-39.9 kg/m(2)); and morbidly obese (≥40 kg/m(2)). 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). The patient's mean ± SD age, weight and BMI were 54 ± 15 years, 90 ± 24 kg and 31 ± 9 kg/m(2), respectively. A two- compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) 0.95 ± 0.48 L/h, volume of distribution of the central compartment (Vc) 15.10 ± 11.78 L, intercompartmental clearance from central to peripheral compartment 5.41 ± 2.28 L/h and intercompartmental clearance from peripheral to central compartment 2.92 ± 4.95 L/h. A fluconazole dose of 200 mg daily was insufficient to achieve fAUC/MIC 100 for pathogens with MICs ≥2 mg/L in patients with BMI >30 kg/m(2) 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/L.