Prospective Cohort Study of Population Pharmacokinetics and Pharmacodynamic Target Attainment of Vancomycin in Adults on Extracorporeal Membrane Oxygenation

Abstract

ABSTRACT The aim of this study was to develop a population pharmacokinetics (PK) model for vancomycin and to evaluate its pharmacodynamic target attainment in adults on extracorporeal membrane oxygenation (ECMO). After a single 1,000-mg dose of vancomycin, samples were collected 9 times per patient prospectively. A population PK model was developed using a nonlinear mixed-effect model. The probability of target attainment (PTA) of vancomycin was evaluated for various dosing strategies using Monte Carlo simulation. The ratio of the area under the vancomycin concentration-time curve at steady state over 24 h to the MIC (AUC/MIC ratio) was investigated by applying the vancomycin breakpoint distribution of MICs for methicillin-resistant Staphylococcus aureus. A total of 22 adult patients with 194 concentration measurements were included. The population PK was best described by a three-compartment model with a proportional residual error model. Vancomycin clearance and steady-state volume of distribution were 4.01 liters/h (0.0542 liters/h/kg) and 29.6 liters (0.400 liters/kg), respectively. If the treatment target AUC/MIC value was only ≥400, a total daily dose of 3 to 4 g would be optimal (PTA of ≥90%) for patients with normal renal function (estimated glomerular filtration rate [eGFR] = 60 to 120 ml/min/1.73 m2) when the MIC was presumed to be 1 mg/liter. However, AUC/MIC values of 400 to 600 were difficult to attain with any dosing strategy regardless of MIC and eGFR. Thus, it is hard to achieve efficacy and safety targets in patients on ECMO using the population dosing approach with Monte Carlo simulations, and therapeutic drug monitoring should be implemented in these patients.