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Introduction <p>Febrile neutropenia (FN) in patients with hematological malignancies is associated with high morbidity and mortality due to bacterial infections, particularly from Gram-negative pathogens. Imipenem is widely used in this setting; however, altered pharmacokinetics in these patients may compromise treatment efficacy, necessitating individualized dosing strategies.</p> Aim <p>This study aimed to develop a population pharmacokinetic model for imipenem in Chinese adult patients with FN and hematological malignancies and to identify optimal pharmacokinetic/pharmacodynamic (PK/PD) targets to guide dosing and predict antimicrobial efficacy.</p> Method <p>A prospective, single-center, open-label study was conducted involving 121 hospitalized patients who contributed 207 plasma samples. Imipenem concentrations were measured by high-performance liquid chromatography. Pharmacokinetic modeling was performed using NONMEM, incorporating patient-specific covariates. Monte Carlo simulations were used to evaluate dosing regimens, and antimicrobial efficacy was assessed based on clinical and microbiological outcomes. The predictive value of PK/PD indices was analyzed using logistic regression and ROC curve analysis.</p> Results <p>A two-compartment model best described imipenem pharmacokinetics. Creatinine clearance (CLCR), gamma-glutamyltransferase (GGT), and vancomycin (VAN) co-administration significantly influenced imipenem clearance. The final model was: CL (L·h<sup>−1</sup>) = 21.36 × (CLCR/110.39)<sup>0.444</sup> × (GGT/55.4)<sup>–0.119</sup> + VAN × 3.78; V1 = 42.9 L, Q = 3.7 L·h<sup>−1</sup>, and V2 = 59 L. The PK/PD index most strongly associated with efficacy was <i>f</i>%T &gt; MIC, with an optimal threshold of 90.48% (AUC<sub>ROC</sub> = 0.728, <i>P</i> = 0.024). Simulation results suggested that a 4&#xa0;g·day<sup>−1</sup> regimen (1000&#xa0;mg q6h, 3-h infusion) is optimal for most patients with MIC ≤ 2&#xa0;mg·L<sup>−1</sup>. However, no standard regimen was effective for <i>Pseudomonas aeruginosa</i> or <i>Acinetobacter baumannii</i> at higher MICs.</p> Conclusion <p>This study highlights the importance of individualized dosing in FN patients with hematological malignancies. CLCR, GGT, and VAN co-administration significantly affect imipenem pharmacokinetics. Achieving <i>f</i>%T &gt; MIC of 90.48% is critical for efficacy. Additional agents may be needed for infections caused by highly resistant organisms such as <i>Pseudomonas aeruginosa</i> and <i>Acinetobacter baumannii</i>.</p>

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Population pharmacokinetics of imipenem and target attainment of pharmacokinetic/pharmacodynamic indices in Chinese adults with febrile neutropenia and hematological malignancies

  • 期刊论文

  • 发表日期：

    2025年10月14日

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  • Qi Rao,
  • Hong Zhu,
  • Lu Jin,
  • Huaijun Zhu,
  • Fang Wu,
  • Jie Zhou,
  • Jinping Zhang,
  • Siliang Wang,
  • Mengying Liu

摘要

Introduction

Febrile neutropenia (FN) in patients with hematological malignancies is associated with high morbidity and mortality due to bacterial infections, particularly from Gram-negative pathogens. Imipenem is widely used in this setting; however, altered pharmacokinetics in these patients may compromise treatment efficacy, necessitating individualized dosing strategies.

Aim

This study aimed to develop a population pharmacokinetic model for imipenem in Chinese adult patients with FN and hematological malignancies and to identify optimal pharmacokinetic/pharmacodynamic (PK/PD) targets to guide dosing and predict antimicrobial efficacy.

Method

A prospective, single-center, open-label study was conducted involving 121 hospitalized patients who contributed 207 plasma samples. Imipenem concentrations were measured by high-performance liquid chromatography. Pharmacokinetic modeling was performed using NONMEM, incorporating patient-specific covariates. Monte Carlo simulations were used to evaluate dosing regimens, and antimicrobial efficacy was assessed based on clinical and microbiological outcomes. The predictive value of PK/PD indices was analyzed using logistic regression and ROC curve analysis.

Results

A two-compartment model best described imipenem pharmacokinetics. Creatinine clearance (CLCR), gamma-glutamyltransferase (GGT), and vancomycin (VAN) co-administration significantly influenced imipenem clearance. The final model was: CL (L·h−1) = 21.36 × (CLCR/110.39)0.444 × (GGT/55.4)–0.119 + VAN × 3.78; V1 = 42.9 L, Q = 3.7 L·h−1, and V2 = 59 L. The PK/PD index most strongly associated with efficacy was f%T > MIC, with an optimal threshold of 90.48% (AUCROC = 0.728, P = 0.024). Simulation results suggested that a 4 g·day−1 regimen (1000 mg q6h, 3-h infusion) is optimal for most patients with MIC ≤ 2 mg·L−1. However, no standard regimen was effective for Pseudomonas aeruginosa or Acinetobacter baumannii at higher MICs.

Conclusion

This study highlights the importance of individualized dosing in FN patients with hematological malignancies. CLCR, GGT, and VAN co-administration significantly affect imipenem pharmacokinetics. Achieving f%T > MIC of 90.48% is critical for efficacy. Additional agents may be needed for infections caused by highly resistant organisms such as Pseudomonas aeruginosa and Acinetobacter baumannii.