TY - JOUR
T1 - Quantification and Explanation of the Variability of First-Dose Amikacin Concentrations in Critically Ill Patients Admitted to the Emergency Department: A Population Pharmacokinetic Analysis
AU - de Winter, Sabrina
AU - van Hest, Reinier
AU - Dreesen, Erwin
AU - Annaert, Pieter
AU - Wauters, Joost
AU - Meersseman, Wouter
AU - van den Eede, Nele
AU - Desmet, Stefanie
AU - Verelst, Sandra
AU - Vanbrabant, Peter
AU - Peetermans, Willy
AU - Spriet, Isabel
N1 - Funding Information: ED is a postdoctoral research fellow of the Research Foundation—Flanders (FWO), Belgium (grant number 12X9420N). The other authors declare that no sources of funding were used to assist with the preparation of the results of this original research. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2021/9
Y1 - 2021/9
N2 - Background: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable. Objective: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV. Methods: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling. Results: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained. Conclusion: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance. Trial Registration: ClinicalTrials.gov ID: NCT02365272.
AB - Background: There may be a difference between the determinants of amikacin exposure in emergency department (ED) versus intensive care (ICU) patients, and the peak amikacin concentration varies widely between patients. Moreover, when the first dose of antimicrobials is administered to septic patients admitted to the ED, fluid resuscitation and vasopressors have just been initiated. Nevertheless, population pharmacokinetic modelling data for amikacin in ED patients are unavailable. Objective: The aim of this study was to quantify the interindividual variability (IIV) in the pharmacokinetics of amikacin in patients admitted to the ED and to identify the patient characteristics that explain this IIV. Methods: Patients presenting at the ED with severe sepsis or septic shock were randomly assigned to receive amikacin 25 mg/kg or 15 mg/kg intravenously. Blood samples were collected at 1, 6 and 24 h after the onset of the first amikacin infusion. Data were analysed using nonlinear mixed-effects modelling. Results: A two-compartment population pharmacokinetic model was developed based on 279 amikacin concentrations from 97 patients. The IIV in clearance (CL) and central distribution volume (V1) were 71% and 26%, respectively. Body mass index (BMI), serum total protein level, serum sodium level, and fluid balance 24 h after amikacin administration explained 30% of the IIV in V1, leaving 18% of the IIV unexplained. BMI and creatinine clearance according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 24 h after amikacin administration explained 46% of the IIV in CL, and 39% remained unexplained. Conclusion: The IIV of amikacin pharmacokinetics in ED patients is large. Higher doses may be considered in patients with low serum sodium levels, low total protein levels, or a high fluid balance. Trial Registration: ClinicalTrials.gov ID: NCT02365272.
UR - http://www.scopus.com/inward/record.url?scp=85111110913&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s13318-021-00698-w
DO - https://doi.org/10.1007/s13318-021-00698-w
M3 - Article
C2 - 34297338
SN - 0378-7966
VL - 46
SP - 653
EP - 663
JO - European Journal of Drug Metabolism and Pharmacokinetics
JF - European Journal of Drug Metabolism and Pharmacokinetics
IS - 5
ER -