Population Pharmacokinetics and Model-Informed Precision Dosing of Colistin Sulfate in Critically Ill Patients with Carbapenem-Resistant Gram-Negative Infections: A Prospective Pharmacokinetic-Pharmacodynamic Study.
- 1Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China.
- 2Department of Intensive Care Unit, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, People's Republic of China.
Abstract
Independently evaluated population pharmacokinetic models and clinically derived pharmacokinetic/pharmacodynamic targets for colistin sulfate remain limited. We aimed to develop and evaluate a model, explore an efficacy threshold, and construct a research model-informed precision dosing calculator. This prospective study included 55 critically ill patients with microbiologically confirmed infection caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) for model development and 15 with suspected CR-GNB infection without microbiological confirmation for independent evaluation of concentration predictions. Plasma concentrations were measured by validated ultra-performance liquid chromatography-tandem mass spectrometry. Modeling used nonlinear mixed-effects modeling software (NONMEM). Logistic regression and receiver operating characteristic (ROC) analysis assessed efficacy predictors and the exploratory threshold. Monte Carlo simulations evaluated probability of target attainment (PTA). A two-compartment model with creatinine clearance (CrCL) as a covariate on clearance (CL) best described the data (typical CL = 6.67 × (CrCL/76.9)0.648 L/h). Independent evaluation yielded a relative root mean square error of 37.4%, with 53.7% of predictions within ±30% of observations. Clinical efficacy was achieved in 24/55 patients. The ratio of 24-hour steady-state area under the concentration-time curve (AUCss,24h) to minimum inhibitory concentration (MIC) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score were independently associated with efficacy (odds ratios per one-unit increase, 1.04 and 0.81, respectively). The exploratory AUCss,24h/MIC cut-off was 40.53 (area under the ROC curve, 0.712). At MIC ≥ 1 mg/L, no evaluated monotherapy regimen achieved PTA ≥ 90% in patients with normal or augmented renal function. This study provides a pharmacokinetic model with preliminary independent predictive evaluation, an exploratory exposure threshold, and an open-access research dosing calculator. Prospective multicenter validation is required before clinical implementation.
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BibTeX
@article{huang2026population,
title = {{Population Pharmacokinetics and Model-Informed Precision Dosing of Colistin Sulfate in Critically Ill Patients with Carbapenem-Resistant Gram-Negative Infections: A Prospective Pharmacokinetic-Pharmacodynamic Study.}},
author = {Tianmin Huang and Lulu Niu and Luyao Qin and Huansheng Feng and Meiquan Wei and Donglan Zhu and Hanchun Wen and Juntao Hu and Zhaoyan Chen and Zhiyong Zhang and Yun Wu and Taotao Liu},
journal = {Drug design, development and therapy},
year = {2026},
month = nov,
doi = {10.2147/dddt.s641015},
url = {https://europepmc.org/article/MED/42999837},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Population Pharmacokinetics and Model-Informed Precision Dosing of Colistin Sulfate in Critically Ill Patients with Carbapenem-Resistant Gram-Negative Infections: A Prospective Pharmacokinetic-Pharmacodynamic Study.
AU - Tianmin Huang
AU - Lulu Niu
AU - Luyao Qin
AU - Huansheng Feng
AU - Meiquan Wei
AU - Donglan Zhu
AU - Hanchun Wen
AU - Juntao Hu
AU - Zhaoyan Chen
AU - Zhiyong Zhang
AU - Yun Wu
AU - Taotao Liu
PY - 2026
DA - 2026/11/03
JO - Drug design, development and therapy
DO - 10.2147/dddt.s641015
UR - https://europepmc.org/article/MED/42999837
AB - Independently evaluated population pharmacokinetic models and clinically derived pharmacokinetic/pharmacodynamic targets for colistin sulfate remain limited. We aimed to develop and evaluate a model, explore an efficacy threshold, and construct a research model-informed precision dosing calculator. This prospective study included 55 critically ill patients with microbiologically confirmed infection caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) for model development and 15 with suspected CR-GNB infection without microbiological confirmation for independent evaluation of concentration predictions. Plasma concentrations were measured by validated ultra-performance liquid chromatography-tandem mass spectrometry. Modeling used nonlinear mixed-effects modeling software (NONMEM). Logistic regression and receiver operating characteristic (ROC) analysis assessed efficacy predictors and the exploratory threshold. Monte Carlo simulations evaluated probability of target attainment (PTA). A two-compartment model with creatinine clearance (CrCL) as a covariate on clearance (CL) best described the data (typical CL = 6.67 × (CrCL/76.9)0.648 L/h). Independent evaluation yielded a relative root mean square error of 37.4%, with 53.7% of predictions within ±30% of observations. Clinical efficacy was achieved in 24/55 patients. The ratio of 24-hour steady-state area under the concentration-time curve (AUCss,24h) to minimum inhibitory concentration (MIC) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) score were independently associated with efficacy (odds ratios per one-unit increase, 1.04 and 0.81, respectively). The exploratory AUCss,24h/MIC cut-off was 40.53 (area under the ROC curve, 0.712). At MIC ≥ 1 mg/L, no evaluated monotherapy regimen achieved PTA ≥ 90% in patients with normal or augmented renal function. This study provides a pharmacokinetic model with preliminary independent predictive evaluation, an exploratory exposure threshold, and an open-access research dosing calculator. Prospective multicenter validation is required before clinical implementation.
SN - 1177-8881
ER -