IV-045 Quan Truong

Underdosing imipenem in patients with renal insufficiency: global clinical data-driven pharmacokinetic/pharmacodynamic study

Anh Quan Truong (1,2,3), Tim J. L. Smeets (1,2), Jean Terrier (4,5), Letao Li (1,2), Xuan Co Dao (6), Jan Strojil (7), Tim Preijers (1,2), Birgit C P Koch (1,2), Angela Huttner (8), Sebastiaan Sassen (1,2)

(1) Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands, (2) Rotterdam Clinical Pharmacometrics Group, Erasmus University Medical Center, Rotterdam, The Netherlands , (3) University of Antwerp, Antwerp, Belgium, (4) Division of General Internal Medicine, Geneva University Hospitals, Geneva, Switzerland, (5) Clinical Pharmacology and Toxicology Service, Anesthesiology Pharmacology and Intensive Care Department, Geneva University Hospitals, Geneva, Switzerland, (6) Intensive Care Unit, Bach Mai Hospital, Hanoi, Vietnam, (7) Department of Pharmacology, Palacky University, Czech Republic, (8) Division of Infectious Diseases, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland

Objectives: Currently, population pharmacokinetic (popPK) models for imipenem in critically ill patients are available. However, they lack a good representation of a wide range of renal functions (1-7). Also, most models are not externally validated. The results from these models are therefore of limited use in clinical settings. Hence, our study aimed to 1) develop a popPK model of imipenem in ICU and non-ICU patients with a wide range of creatinine clearance, and 2) assess the target attainment of current highest dosing regimens across different renal functions.

Methods: A dataset from Switzerland was used to develop a popPK model for imipenem and two datasets (Czech Republic and Vietnam) were used for external validation. Patients with extracorporeal membrane oxygenation or renal replacement therapies were excluded. Non-linear mixed-effect modelling was applied using NONMEM v7.5 (ICON Development Solutions, Ellicott City, MD, USA). Monte Carlo simulations were performed to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) against the minimum inhibitory concentration (MIC) distribution of Pseudomonas aeruginosa (8, 9), across a wide range of renal functions (15-130 mL/min). Currently licensed doses (i.e. 1000mg q6h, 750mg q8h, 500mg q6h and 500mg q12h) were simulated. The pharmacokinetic/pharmacodynamic (PK/PD) targets of 40% and 100% for the fraction of the time free drug concentrations remained above the minimum inhibitory concentration (ƒT>MIC) were evaluated. Adequate doses were achieved if at least 90% PTA and CFR were obtained.

Results: Model development utilised plasma PK data from 322 concentrations of 151 patients in Switzerland, with external validation performed on 111 concentrations of 19 patients from the Czech Republic and 85 concentrations of 43 patients from Vietnam. A two-compartment popPK model comprising an exponential residual error model on log-transformed concentration best described the data. Imipenem clearance was estimated at 14.6 L/h and intercompartmental clearance at 2.92 L/h. The volumes of distribution for the central and peripheral compartments were 28.7 L and 21.4 L, respectively. The Cockcroft-Gault creatinine clearance significantly improved the model and reduced the inter-individual variability of imipenem clearance (from 44.8% to 35.9%). The developed model performed well on two external validation datasets. Dosing simulations indicated that with a 40% ƒT>MIC target, all regimens achieved at least 90% PTA at a MIC of 2 mg/L. However, with a 100% ƒT>MIC target, the regimen of 500 mg q6h at 30-60 mL/min covered up to a MIC of 1 mg/L, irrespective of infusion time, as did the regimen of 1000 mg q6h at 90-130 mL/min. For CFR, all licensed dosing regimens could cover the susceptible P. aeruginosa (MIC ≤ 4 mg/L) for the 40% ƒT>MIC target, but none of them could cover the target of 100% ƒt>MIC.

Conclusions: A two-compartment popPK model, capturing a wide range of renal functions in a heterogeneous population (ICU and non-ICU) was developed. Using simulations, the current recommended dose for renal insufficient patients could not adequately achieve the 100% ƒT>MIC at MIC of 2 mg/L. These findings highlight the necessity for optimizing imipenem dosing through further investigation, particularly in patients with renal insufficiency.

References:

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  8. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 13.1, 2023 2023 [Available from: http://www.eucast.org.
  9. European Committee on Antimicrobial Susceptibility Testing. Data from the EUCAST MIC distribution website 2023 [Available from: http://www.eucast.org.

Reference: PAGE 32 (2024) Abstr 11176 [www.page-meeting.org/?abstract=11176]

Poster: Clinical Applications

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