Background: Vancomycin is the most commonly prescribed intravenous (IV) antibiotic in the high-flux haemodialysis (HFHD) setting. The aim of this study was to develop a population pharmacokinetic (PK) model for vancomycin in HFHD to examine the probability of target attainment (PTA) of several dosing regimens of vancomycin to optimise dosing.
Methods: Data were collected retrospectively from 37 patients receiving HFHD at the Royal Melbourne Hospital and Western Hospital. The data was analysed using non-linear mixed effects modelling (NONMEM version 7.3) to develop a population PK model. Several clinically relevant dosing regimens were examined using Monte Carlo simulations to determine the PTA for vancomycin over a period of 8 days. The PTA for vancomycin was an AUC/MIC24hour ≥400 for micro-organisms with an MIC of 1mg/L with success defined as a PTA of ≥90%. Fixed dosing (e.g. 1g for all patients), weight-based dosing (i.e. mg/kg dosing) and a combination of the two were explored. Vancomycin doses were administered either during or immediately after HFHD.
Results: The data were best described using a two-compartment model with a proportional error model and with between-subject variability on non-HFHD clearance (CL), central compartment volume (V1) and peripheral compartment volume (V2). Lean body weight was included as a covariate on non-HFHD CL, V1 and V2. The estimated parameters from the final model were: 0.44L/h (non-HFHD CL), 3.86L/h (HFHD CL), 45.3L (V1), 45.6L (V2) and 4.93L/h (intercompartmental CL). Fixed dosing of vancomycin resulted in the PTA being ≤90% for most days of therapy. Whilst weight-based dosing resulted in the PTA being ≥90% on all days, there were concerns with supratherapeutic concentrations with repeated doses of vancomycin. A combination of a weight-based loading dose of 30mg/kg and a fixed maintenance dose of 1g afforded the PTA being ≥90% on all days when a HFHD session occurred within 24 hours of the first dose. When the first HFHD session was delayed by 2-3 days post loading dose, the PTA fell below 90% on days 2-3 of therapy. An additional vancomycin dose of 500mg administered on each non-HFHD day prior to the first HFHD session resulted in the PTA being ≥90% for all 8 days.
Conclusions: In the HFHD setting, a weight-based loading dose of 30mg/kg and a maintenance dose of 1g on HFHD days appears suitable for vancomycin. However, if there is more than 1 day delay between the loading dose and the first HFHD session, an additional 500mg dose should be administered on each non-HFHD day to ensure the PTA remains above 90%.