International journal of clinical pharmacy · 2025
Population pharmacokinetics of imipenem and target attainment of pharmacokinetic/pharmacodynamic indices in Chinese adults with febrile neutropenia and hematological malignancies.
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Rao Qi, Zhu Hong, Jin Lu, Zhu Huaijun, Wu Fang, Zhou Jie, Zhang Jinping, Wang Siliang, Liu Mengying
Аннотация
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.
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.