Population pharmacokinetics and dose simulation of vancomycin in critically ill patients during high-volume haemofiltration

Abstract

This study aimed to describe the population pharmacokinetics of vancomycin in critically ill patients with refractory septic shock undergoing continuous venovenous high-volume haemofiltration (HVHF) and to define appropriate dosing for these patients. This was a prospective pharmacokinetic study in the ICU of a university hospital. Eight blood samples were taken over one vancomycin dosing interval. Samples were analysed by a validated liquid chromatography–tandem mass spectrometry assay. Non-linear mixed-effects modelling was used to describe the population pharmacokinetics. Dosing simulations were used to define therapeutic vancomycin doses for different HVHF settings. Nine patients were included (five male). The mean weight and SOFA score were 70kg and 11, respectively. Mean HVHF settings were: blood flow rate, 240mL/min; and haemofiltration exchange rate, 100mL/kg/h. A linear two-compartment model with zero-order input adequately described the data. Mean parameter estimates were: clearance, 2.9L/h; volume of distribution of central compartment (V1), 11.8L; volume of distribution of peripheral compartment (V2), 18.0L; and intercompartmental clearance, 9.3L/h. HVHF intensity was strongly associated with vancomycin clearance (P<0.05) and was a covariate in the final model. Simulations indicate that after a loading dose, vancomycin doses required for different HVHF intensities would be 750mg every 12h (q12h) for 69mL/kg/h, 1000mg q12h for 100mL/kg/h and 1500mg q12h for 123mL/kg/h. Continuous infusion would also be a valuable administration strategy. In conclusion, variable and much higher than standard vancomycin doses are required to achieve therapeutic concentrations during different HVHF settings.