Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy

Claire Roger, Steven C. Wallis, Laurent Muller, Gilbert Saissi, Jeffrey Lipman, Jean-Yves Lefrant, Jason A. Roberts

To describe amikacin pharmacokinetics in critically ill patients receiving equal doses (30 ml/kg/h) of continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodiafiltration (CVVHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using Pmetrics. Sixteen patients and twenty sampling intervals were analysed (9 CVVH, 11 CVVHDF). A two-compartment linear model best described the data. Patient weight was the only covariate that was associated with drug clearance. The mean (SD) parameter estimates were 25.2 ± 17.3 L for central volume, 0.89 ± 1.17 h(-1) (kcp) and 2.38 ± 6.60 h(-1) (kpc) for intercompartimental rate constants, 4.45 ± 2.35 L/h for hemodiafiltration clearance and 4.69 ± 2.42 L/h for hemofiltration clearance. Dosing simulations for amikacin supported the use of high dosing regimens (≥25mg/kg) and extended intervals (36 to 48h) for most patients when considering pharmacokinetics/pharmacodynamics (PK/PD) targets of Cmax/MIC ≥ 8 and a minimal concentration ≤ 2.5 mg/L at the end of the dosing interval.The mean clearance of amikacin was 1.8 ± 1.3 L/h by CVVHDF and 1.3 ± 1 L/h by CVVH, respectively. Based on simulations, a strategy of an extended-interval high loading dose of amikacin (25 mg/kg 48-hourly) associated with therapeutic drug monitoring (TDM) should be the preferred approach for aminoglycoside in critically ill patients receiving continuous renal replacement therapy (CRRT).