Enteral fluconazole population pharmacokinetics in patients in the surgical intensive care unit

Study Objective. To determine the population pharmacokinetic parameters of enterally administered fluconazole in patients in a surgical intensive care unit (SICU). Design. Population pharmacokinetics component of a prospective, randomized clinical study. Setting. The SICU at a university hospital. Patients. One hundred ten patients with an expected length of stay in the SICU of 3 or more days and a need for intubation, in whom at least one fluconazole plasma concentration-time measurement was available. Intervention. Patients received fluconazole as an 800-mg loading dose and as a 200- or 400-mg (depending on renal function) daily maintenance dose. Fluconazole suspension was administered enterally followed by a 30-ml free water flush. Measurements and Main Results. Plasma samples were collected, and population pharmacokinetic analysis was performed with NONMEM software; a one-compartment pharmacokinetic model was used. Fluconazole clearance was dependent on creatinine clearance, and volume of distribution was dependent on body weight and age. In patients with creatinine clearance values greater than 80 ml/minute, between 30 and 80 ml/minute, and less than 30 ml/minute, geometric mean (percentage coefficient of variation) fluconazole clearance was 14.39 ml/minute (21%), 10.53 ml/minute (28%), and 5.47 ml/minute (30%), respectively The geometric mean (percentage coefficient of variation) volume of distribution in all patients was 1.27 L/kg (28%) and decreased with increasing age. Conclusions. Fluconazole clearance values in patients in the SICU who had normal renal function and in those with renal impairment were in agreement with previously reported data. Fluconazole volume of distribution was larger and half-life was longer in the SICU population than in healthy subjects.