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Updated: Jun 28, 2025
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
A systematic evaluation of population pharmacokinetic models for polymyxin B in patients with liver and/or kidney
Xueyong Li1,2, Yu Cheng1, Bingqing Zhang1,2
1Department of Pharmacy, Fujian Medical University Union Hospital, 29 Xin Quan Rd, Fuzhou, 350001, Fujian, People's Republic of China.
Abstract:
Polymyxin B (PMB) is considered a last-line treatment for multidrug-resistant (MDR) gram-negative bacterial infections. Model-informed precision dosing with population pharmacokinetics (PopPK) models could help to individualize PMB dosing regimens and improve therapy. However, the external prediction ability of the established PopPK models has not been fully elaborated. This study aimed to systemically evaluate eleven PMB PopPK models from ten published literature based on a new independent population, which was divided into four different populations, patients with liver dysfunction, kidney dysfunction, liver and kidney dysfunction, and normal liver and kidney function. The whole data set consisted of 146 patients with 391 PMB concentrations. The prediction- and simulation-based diagnostics and Bayesian forecasting were conducted to evaluate model predictability. In the overall evaluation process, none of the models exhibited satisfactory predictive ability in both prediction- and simulation-based diagnostic simultaneously. However, the evaluation of the models in the subgroup of patients with normal liver and kidney function revealed improved predictive performance compared to those with liver and/or kidney dysfunction. Bayesian forecasting demonstrated enhanced predictability with the incorporation of two to three prior observations. The external evaluation highlighted a lack of consistency between the prediction results of published models and the external validation dataset. Nonetheless, Bayesian forecasting holds promise in improving the predictive performance of the models, and feedback from therapeutic drug monitoring is crucial in optimizing individual dosing regimens.
Insights
Established Polymyxin B (PMB) population pharmacokinetic (PopPK) models lack external predictive ability, especially in patients with organ dysfunction. Bayesian forecasting shows promise for improving PMB dosing accuracy with prior data.
Area of Science:
- Pharmacology
- Infectious Diseases
- Clinical Pharmacy
Background:
- Polymyxin B (PMB) is a critical last-line antibiotic for multidrug-resistant (MDR) Gram-negative infections.
- Population pharmacokinetic (PopPK) models aim to optimize PMB dosing for improved patient outcomes.
- The external predictive performance of existing PMB PopPK models requires thorough evaluation.
Purpose of the Study:
- To systematically evaluate eleven published PMB PopPK models using an independent patient cohort.
- To assess model predictability across different patient subgroups: normal function, liver dysfunction, kidney dysfunction, and combined dysfunction.
- To investigate the utility of Bayesian forecasting for enhancing PMB dosing predictions.
Main Methods:
- External validation of eleven PMB PopPK models against a dataset of 146 patients (391 concentrations).
- Stratified analysis of model performance in four distinct patient populations.
- Application of prediction- and simulation-based diagnostics and Bayesian forecasting for model evaluation.
Main Results:
- No single model demonstrated satisfactory predictive ability across both prediction and simulation diagnostics overall.
- Models showed better predictive performance in patients with normal liver and kidney function compared to those with dysfunction.
- Bayesian forecasting improved predictability, particularly when incorporating two to three prior observations.
Conclusions:
- Existing PMB PopPK models exhibit limited external predictive consistency, especially in patients with hepatic or renal impairment.
- Bayesian forecasting offers a viable strategy to enhance the predictive accuracy of PMB dosing models.
- Therapeutic drug monitoring remains essential for refining individual PMB dosage regimens.
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