Population Pharmacokinetics of Imipenem in Solid Tumor Patients with Infections: A Real-World Study.

Abstract

Objectives: To characterize the population pharmacokinetics (PPK) of imipenem in critically ill solid tumor patients and to optimize dosing regimens through pharmacodynamic analysis.

Methods: A PPK model was developed using nonlinear mixed-effects modeling (Monolix 2023R1) based on 25 critically ill solid tumor patients with infections. Model selection used objective function value (OFV), Akaike/Bayesian information criteria(AIC/BIC), and goodness-of-fit diagnostics. Covariate screening involved a dual-algorithm approach (SAMBA and COSSAC) for validation. Monte Carlo simulations (n=10,000) evaluated the probability of target attainment (PTA) for 100% fT>MIC across different renal function groups.

Results: A linear one-compartment model best described imipenem pharmacokinetics. Typical population estimates were clearance (CL) = 2.7 L/h and volume of distribution (Vd) = 10.6L-significantly lower than values reported in general critical care populations. Creatinine clearance (CLCR) and septic shock were identified as significant covariates affecting CL. Severe malnutrition contributed to reduced Vd. Simulations revealed: For MIC ≤2 mg·L⁻¹, 500 mg q6h achieved PTA >90% when CLCR >30 mL/min; for MIC=4 mg·L⁻¹, 1000 mg q6h was required for patients with CLCR >60 mL/min (PTA=94.9-100%); no regimen achieved PTA >20% for MIC ≥16 mg·L⁻¹.

Conclusion: This study highlights the significant effect of specific pathophysiological changes in solid tumor patients (such as cachexia-induced reduction in volume of distribution) on drug disposition, providing essential evidence for informing personalized imipenem dosing in this vulnerable group to improve efficacy and reduce resistance risks.