Dose Optimization of Amikacin in the Emergency Department: A Population Pharmacokinetics Simulation Study.

Autor:	Dia N; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven., De Winter S; Pharmacy Department, University Hospitals Leuven., Gijsen M; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven.; Pharmacy Department, University Hospitals Leuven., Desmet S; University Hospitals Leuven, National Reference Centre for Streptococcus Pneumonia.; Department of Microbiology, Immunology and Transplantation, KU Leuven; and., Vanbrabant P; Department of Microbiology, Immunology and Transplantation, KU Leuven; and.; Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium., Peetermans W; Department of Microbiology, Immunology and Transplantation, KU Leuven; and.; Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium., Spriet I; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven.; Pharmacy Department, University Hospitals Leuven., Dreesen E; Department of Pharmaceutical and Pharmacological Sciences, KU Leuven.
Jazyk:	angličtina
Zdroj:	Therapeutic drug monitoring [Ther Drug Monit] 2024 Dec 03. Date of Electronic Publication: 2024 Dec 03.
DOI:	10.1097/FTD.0000000000001279
Abstrakt:	Background: In adult patients with sepsis or septic shock admitted to the emergency department, a single intravenous 15 mg/kg amikacin dose provides inadequate pharmacokinetic-pharmacodynamic target attainment at the locally reported minimum inhibitory concentration (MIC) of 2 mg/L and the European Committee on Antimicrobial Susceptibility Testing clinical breakpoint for Enterobacterales of 8 mg/L. Objectives: To provide an amikacin dosing strategy with a clinically acceptable probability of target attainment (PTA) for all patients. Methods: Stochastic simulations were performed using a two-compartment population pharmacokinetics model of amikacin (NONMEM 7.5). PTA was evaluated for various dosing strategies across a range of virtual patients' body weight, body mass index, serum total protein, serum sodium, fluid balance, and estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI), at the locally reported MIC of 2 mg/L and the clinical breakpoint of 8 mg/L. The pharmacokinetic-pharmacodynamic targets were a 24-hour area under the concentration-time curve (AUC24h)/MIC of ≥80 and a 24-hour postdose concentration (C24h) of < 3 mg/L for efficacy and safety, respectively. Results: The PTA for the clinical breakpoint of 8 mg/L was <90% with standard 15 mg/kg dosing, across all patient characteristics. A flat 1500-mg dose achieved ≥90% PTA for the entire population at a MIC of 2 mg/L. However, at the clinical breakpoint of 8 mg/L, a flat 3500-mg dose provided ≥90% PTA only when the eGFRCKD-EPI was <96 mL/min/1.73 m2. The C24h was similar for 1500 mg and 15 mg/kg dosing, whereas 3500 mg resulted in a higher C24h. Conclusions: A flat dose is recommended over weight-based dosing. However, selecting a 1500-mg or 3500-mg dose may compromise either efficacy (MIC 2 mg/L) or safety (clinical breakpoint 8 mg/L), posing a dilemma. Clinical validation is warranted. Competing Interests: I. Spriet received consultancy support and lecture fees from argenx, Pfizer, Merck, and Cidara. E. Dreesen received consultancy fees from Alimentiv and argenx, lecture fees from Celltrion and Galapagos, and financial support from Janssen, R-Biopharm, and Prometheus (all honoraria/fees paid to the University). The remaining authors declare no conflict of interest. (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)
Databáze:	MEDLINE
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