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

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/m(2)), obese (30.0 to 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) patients. The patients mean +/- standard deviation (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) of 0.95 +/- 0.48 liter/h, volume of distribution of the central compartment (V-c) 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/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/liter.