Population Pharmacokinetics of Fosfomycin in Critically Ill Patients

Abstract

e This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CL CR ) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (V c ) described the data adequately. Calculated CL CR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, V c of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

Pharmacodynamic Evaluation of the Potential Clinical Utility of Fosfomycin and Meropenem in Combination Therapy against KPC-2-Producing Klebsiella pneumoniae

“…The predicted C max may be sensitive to the number of compartments used in the model. C max is also affected by the duration of infusion The distribution phase, however, is no longer apparent when the drugs are infused for more than half an hour, since the intercompartmental clearance rates reported for the two drugs are very high (24,57). Moreover, the V for both drugs is low, indicating that the drugs are distributed extracellularly.…”

“…The population pharmacokinetic parameters of meropenem and fosfomycin used in the simulation were obtained from critically ill patients previously described in the literature (20,24) and were used for simulations of pharmacodynamic surrogate indices of 20,000 virtual patients subdivided into 10,000 patients with normal renal function and 10,000 with mild to moderate renal impairment. Figure 1 shows the distribution of creatinine clearance based on the MDRD computation for male and female patients with nor- mal renal function and mild to moderate renal impairment.…”

“…The pharmacokinetic parameters of meropenem and fosfomycin used for the simulation came from one-and two-compartment models, respectively, previously developed from a critically ill population (20,24). Other studies used a two-compartment model to characterize the total concentration of meropenem in plasma (55)(56)(57)(58).…”

“…The population pharmacokinetic model of fosfomycin in critically ill patients from the report of Parker et al (24) was used to simulate 20,000 virtual patient profiles. Their model reported seven interoccasion CL parameters.…”

Translating innovative pharmacokinetic sampling techniques into improved antibiotic dosing regimens in critically ill patients

“…The final aim is to describe practical issues associated with use of VAMS. We can report that critically ill patients experiencing renal insufficiency while receiving multiple doses of fosfomycin can exhibit very high concentrations (>1000 µg/mL) in their plasma [135] and this has led to the unusually high concentration range described here.…”