Population pharmacokinetic/pharmacodynamic evaluations of amikacin dosing in critically ill patients undergoing continuous venovenous hemodiafiltration.

OBJECTIVES:The pharmacokinetics/pharmacodynamics (PK/PD) of amikacin in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF) are poorly described, and appropriate dosing is unclear in this patient population. This study aimed to develop a population PK model of amikacin and to provide systemic PK/PD evaluations for different dosing regimens in CVVHDF patients. METHODS:One hundred and sixty-one amikacin concentration observations from thirty-three CVVHDF patients were pooled to develop the population PK model. Monte Carlo simulations were performed to assess the PK/PD index-based efficacy (Cmax/minimal inhibitory concentration (MIC) > 8 and AUC/MIC > 58.3), nonrisk of drug resistance (T>MIC > 60%) and risk of toxicity (trough concentration > 5 mg/l) for different dosing regimens. KEY FINDINGS:A two-compartment model adequately described the concentration data of amikacin. A loading dose of at least 25 mg/kg amikacin is needed to reach the efficacy targets in CVVHDF patients for an MIC of 4 mg/l, and the studied doses could not provide adequate drug exposure and T>MIC > 60% for an MIC ≥ 8 mg/l. The risk of toxicity for amikacin was unacceptably high for the patient population with low clearance. CONCLUSIONS:Our study demonstrated that a loading dose of 25-30 mg/kg amikacin is needed to provide adequate PK/PD target attainment in CVVHDF patients for an MIC ≤ 4 mg/l.