Using population pharmacokinetics to dose gentamicin 1 during extended - daily diafiltration in critically ill patients with 2 acute kidney injury

28 The objective of this prospective pharmacokinetic study was to describe the variability of 29 gentamicin plasma concentrations in critically ill patients with AKI necessitating extended30 daily-diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently 31 perform Monte Carlo dosing simulations to determine which dose regimen achieves 32 pharmacodynamic targets most consistently. We collected data from 28 gentamicin doses in 14 33 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma 34 samples were collected. A population pharmacokinetic model was used to describe the 35 pharmacokinetics of gentamicin and perform Monte-Carlo dosing simulations between 3mg/kg 36 and 7mg/kg and at various time points before commencement of EDD-f to evaluate the optimal 37 dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic 38 model described gentamicin clearance on and off EDD-f adequately. The plasma half-life of 39 gentamicin during EDD-f was 13.8-hours compared with 153.4-hours without EDD-f. Monte40 Carlo simulations suggest that 48-hourly 6mg/kg dosing either 30-minutes or one-hour before 41 the commencement of EDD-f results in 100% attainment of Cmax (<10mg/L) targets and 42 sufficient attainment of AUC0-24 (70-120 mg.h/L) targets. None of the simulated dosing 43 regimens achieved satisfactory Cmin targets (<1.0mg/L) at 24-hours. In conclusion, dosing 44 gentamicin 30-minutes to one-hour before the commencement of an EDD-f treatment enables 45 attainment of target peak concentrations for maximal therapeutic effect, whilst enhancing drug 46 clearance to minimize toxicity. Re-dosing in many patients should occur after 48-hours and we 47 would recommend use of therapeutic drug monitoring to guide dosing to optimize achievement 48 of AUC0-24 targets. 49 on N ovem er 2, 2017 by gest httpaac.asm .rg/ D ow nladed fom