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

Abstract

The objective of this study was to describe amikacin pharmacokinetics (PK) in critically ill patients receiving equal doses (30 ml/kg of body weight/h) of continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF). Patients receiving amikacin and undergoing CVVH or CVVHDF were eligible. Population pharmacokinetic analysis and Monte Carlo simulation were undertaken using the Pmetrics software package for R. Sixteen patients (9 undergoing CVVH, 11 undergoing CVVHDF) and 20 sampling intervals were analyzed. A two-compartment linear model best described the data. Patient weight was the only covariate that was associated with drug clearance. The mean ± standard deviation parameter estimates were 25.2 ± 17.3 liters for the central volume, 0.89 ± 1.17 h(-1) for the rate constant for the drug distribution from the central to the peripheral compartment, 2.38 ± 6.60 h(-1) for the rate constant for the drug distribution from the peripheral to the central compartment, 4.45 ± 2.35 liters/h for hemodiafiltration clearance, and 4.69 ± 2.42 liters/h for hemofiltration clearance. Dosing simulations for amikacin supported the use of high dosing regimens (≥25 mg/kg) and extended intervals (36 to 48 h) for most patients when considering PK/pharmacodynamic (PD) targets of a maximum concentration in plasma (Cmax)/MIC ratio of ≥8 and a minimal concentration of ≤2.5 mg/liter at the end of the dosing interval. The mean clearance of amikacin was 1.8 ± 1.3 liters/h by CVVHDF and 1.3 ± 1 liters/h by CVVH. On the basis of simulations, a strategy of an extended-interval high loading dose of amikacin (25 mg/kg every 48 h) associated with therapeutic drug monitoring (TDM) should be the preferred approach for aminoglycoside treatment in critically ill patients receiving continuous renal replacement therapy (CRRT). (This study is a substudy of a trial registered at ClinicalTrials.gov under number NCT01403220.).

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Figures

FIG 1

Observed mean concentration-time profiles for the amikacin dosing sampling interval in critically ill patients receiving CVVH (n = 9) or CVVHDF (n = 11). Error bars represent standard deviations.

FIG 2

Diagnostic plots for the final covariate model. Observed versus population predicted concentrations (top right) and individual predicted concentrations (top left) in plasma. (Bottom) Visual predictive check. CI, confidence interval. Inter, intercept.

FIG 3

PTA of efficacy (Cmax/MIC ratio ≥ 8) and toxicity (Cmin ≥ 2.5 mg/liter at the end of the dosing interval) for a patient undergoing CVVH with a body weight of 80 kg with dosing every 24 h (q24) (a), 36 h (q36) (b), and 48 h (q48) (c) and targeting pathogens with an MIC of 4 mg/liter.

FIG 4

PTA of efficacy (Cmax/MIC ratio ≥ 8) and toxicity (Cmin ≥ 2.5 mg/liter at the end of the dosing interval) for a patient undergoing CVVHDF with a body weight of 80 kg with dosing every 24 h (a), 36 h (b), and 48 h (c) and targeting pathogens with an MIC of 4 mg/liter. Units for dosing are milligrams per kilogram.