Population Pharmacokinetics of Amikacin in Patients on Veno-Arterial Extracorporeal Membrane Oxygenation

Abstract

Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support leads to complex pharmacokinetic alterations, whereas adequate drug dosing is paramount for efficacy and absence of toxicity in critically ill patients. Amikacin is a major antibiotic used in nosocomial sepsis, especially for these patients. We aimed to describe amikacin pharmacokinetics on V-A ECMO support and to determine relevant variables to improve its dosing. All critically ill patients requiring empirical antimicrobial therapy, including amikacin for nosocomial sepsis supported or not by V-A ECMO, were included in a prospective population pharmacokinetic study. This population pharmacokinetic analysis was built with a dedicated software, and Monte Carlo simulations were performed to identify doses achieving therapeutic plasma concentrations. Thirty-nine patients were included (control n = 15, V-A ECMO n = 24); 215 plasma assays were performed and used for the modeling process. Patients received 29 (24-33) and 32 (30-35) mg/kg of amikacin in control and ECMO groups, respectively. Data were best described by a two-compartment model with first-order elimination. Inter-individual variabilities were observed on clearance, central compartment volume (V₁)_, and peripherical compartment volume (V₂). Three significant covariates explained these variabilities: Kidney Disease Improving Global Outcomes (KDIGO) stage on amikacin clearance, total body weight on V_1, and ECMO support on V₂. Our simulations showed that the adequate dosage of amikacin was 40 mg/kg in KDIGO stage 0 patients, while 25 mg/kg in KDIGO stage 3 patients was relevant. V-A ECMO support had only a secondary impact on amikacin pharmacokinetics, as compared to acute kidney injury.

Keywords: Bayesian modelization; amikacin; extracorporeal membrane oxygenation; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; sepsis; therapeutic drug monitoring.

Figure 1

Individual concentration-time curves of amikacin in plasma (black color for V-A ECMO, red color for control): (A) arithmetic scale, (B) logarithmic scale.

Figure 2

Prediction Corrected Visual Predictive Check of final model.

Figure 3

Bayesian estimates of the final model in control (top row) and V-A ECMO (bottom row) patients as a function of KDIGO stage (column).

Figure 4

Dose simulations (A) at 35 mg/kg and 40 mg/kg in KDIGO stage 0 control (G0K0, top) and V-A ECMO (G1K0, bottom) patients vs. 30 mg/kg (B) at 25 mg/kg in KDIGO stage 3 control (G0K0, top) and V-A ECMO (G3K0, bottom) patients vs. 30 mg/kg.