Caleb J P Economou1, Jan T Kielstein2, David Czock3, Jiao Xie4, Jonathan Field5, Brent Richards5, Mandy Tallott5, Adam Visser5, Christina Koenig6, Carsten Hafer2, Julius J Schmidt7, Jeffrey Lipman8, Jason A Roberts9. 1. University of Queensland Centre for Clinical Research, Faculty of Medicine, Australia; ICON Cancer Foundation, Department of Research, Brisbane, Queensland, Australia. 2. Medical Clinic V, Nephrology, Rheumatology and Blood Purification, Academic Teaching Hospital Braunschweig, Braunschweig, Germany. 3. Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany. 4. University of Queensland Centre for Clinical Research, Faculty of Medicine, Australia. 5. Department of Intensive Care Medicine, Gold Coast University Hospital, Gold Coast, Queensland, Australia. 6. Department of Intensive Care Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; Hospital Pharmacy, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. 7. Department of Nephrology, Hannover Medical School, Hannover, Germany. 8. University of Queensland Centre for Clinical Research, Faculty of Medicine, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. 9. University of Queensland Centre for Clinical Research, Faculty of Medicine, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Department of Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia; Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia. Electronic address: j.roberts2@uq.edu.au.
Abstract
OBJECTIVES: The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically ill patients with acute kidney injury. METHODS: Critically ill patients prescribed vancomycin across two sites had blood samples collected during one to three dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics®. The target vancomycin exposures were the area under the concentration-time curve within a 24-h period (AUC0-24)/minimum inhibitory concentration (MIC) ratio of 400 for efficacy and AUC0-24 700 for toxicity. RESULTS: Eleven critically ill patients (seven male) were enrolled and contributed 192 plasma samples. The patient's mean ± standard deviation (SD) age, weight and body mass index (BMI) were 57 ± 13 years, 98 ± 43 kg and 31 ± 9 kg/m2, respectively. A two-compartment linear model adequately described the data. The mean ± SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 ± 1.99 L/h, non-PIRRT CL 2.15 ± 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 ± 24.33 L, distribution rate constant from central to peripheral compartment 5.97 ± 7.93 per h and from peripheral to central compartment 5.29 ± 6.65 per h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg per day are suggested to be efficacious, whilst minimising toxic, exposures. CONCLUSIONS: This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT, should be selected and supplemented with therapeutic drug monitoring.
OBJECTIVES: The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically illpatients with acute kidney injury. METHODS:Critically illpatients prescribed vancomycin across two sites had blood samples collected during one to three dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics®. The target vancomycin exposures were the area under the concentration-time curve within a 24-h period (AUC0-24)/minimum inhibitory concentration (MIC) ratio of 400 for efficacy and AUC0-24 700 for toxicity. RESULTS: Eleven critically illpatients (seven male) were enrolled and contributed 192 plasma samples. The patient's mean ± standard deviation (SD) age, weight and body mass index (BMI) were 57 ± 13 years, 98 ± 43 kg and 31 ± 9 kg/m2, respectively. A two-compartment linear model adequately described the data. The mean ± SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 ± 1.99 L/h, non-PIRRT CL 2.15 ± 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 ± 24.33 L, distribution rate constant from central to peripheral compartment 5.97 ± 7.93 per h and from peripheral to central compartment 5.29 ± 6.65 per h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg per day are suggested to be efficacious, whilst minimising toxic, exposures. CONCLUSIONS: This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT, should be selected and supplemented with therapeutic drug monitoring.
Authors: Vesa Cheng; Mohd H Abdul-Aziz; Fay Burrows; Hergen Buscher; Young-Jae Cho; Amanda Corley; Arne Diehl; Eileen Gilder; Stephan M Jakob; Hyung-Sook Kim; Bianca J Levkovich; Sung Yoon Lim; Shay McGuinness; Rachael Parke; Vincent Pellegrino; Yok-Ai Que; Claire Reynolds; Sam Rudham; Steven C Wallis; Susan A Welch; David Zacharias; John F Fraser; Kiran Shekar; Jason A Roberts Journal: Antimicrob Agents Chemother Date: 2021-10-11 Impact factor: 5.938