Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy.
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.).
Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia claire.roger@chu-nimes.fr.
Claire
C
Roger
Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
Steven C
SC
Wallis
Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France.
Laurent
L
Muller
Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France.
Gilbert
G
Saissi
Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia Department of Intensive Care Medicine, Royal Brisbane and Womens' Hospital, Brisbane, Queensland, Australia.
Jeffrey
J
Lipman
Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France.
Jean-Yves
JY
Lefrant
Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Queensland, Australia School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia Department of Intensive Care Medicine, Royal Brisbane and Womens' Hospital, Brisbane, Queensland, Australia Pharmacy Department, Royal Brisbane and Womens' Hospital, Brisbane, Queensland, Australia.
Jason A
JA
Roberts
D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D000583:Amikacin / Q000493:pharmacokinetics / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016638:Critical Illness; D017583:Hemodiafiltration / Q000379:methods; D006440:Hemofiltration / Q000379:methods; D007668:Kidney / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009010:Monte Carlo Method; D017582:Renal Replacement Therapy / Q000379:methods; D016032:Randomized Controlled Trials as Topic
D000583:Amikacin; D000900:Anti-Bacterial Agents