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A systematic evaluation of population pharmacokinetic models for polymyxin B in patients with liver and/or kidney dysfunction

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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.

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All datasets analyzed in this study are included in the article/Supplementary Material.

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Funding

This study was supported by the Joint Funds for the Innovation of Science and Technology, Fujian Province (Grant No. 2019Y9051), Guiding Project of Science and Technology, Fujian Province (Grant No. 2021Y0019), and Fujian Natural Science Foundation Project (Grant No. 2021J01761).

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  1. Xueyong Li and Yu Cheng contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Fujian Medical University Union Hospital, 29 Xin Quan Rd, Fuzhou, 350001, Fujian, People’s Republic of China

    Xueyong Li, Yu Cheng, Bingqing Zhang, Hailing Lin, Maobai Liu, Wancai Que & Hongqiang Qiu

  2. College of Pharmacy, Fujian Medical University, Fuzhou, 350004, People’s Republic of China

    Xueyong Li, Bingqing Zhang, Bo Chen, Yiying Chen, Yingbing Huang & Hongqiang Qiu

  3. Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China

    Lili Zhou & Hui Zhang

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Contributions

Conceptualization, H. Q., H. Z., and Q. W.; methodology, X. L., Y. C., and B. Z.; software, X. L.; validation, B. Z. and Y. C.; formal analysis, B. C. and L. Z.; investigation, Y. C. and H. L.; resources, Y. C. and Y. H.; data curation, X. L.; writing—original draft preparation, X. L.; writing—review and editing, H. Q.; visualization, X. L.; supervision, H. Z., M. L. and H. Q.; project administration, W. Q.; funding acquisition, Y. C. and H. Q. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Wancai Que or Hongqiang Qiu.

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The authors declare no competing interests.

Ethics statement

The studies involving human participants were reviewed and approved by the Fujian Medical University Union Hospital Research and Ethics Committee on 31-Mar-2021 (No. 2021KJT052). Patients or their relatives provided written informed consent to participate in the study.

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Li, X., Cheng, Y., Zhang, B. et al. A systematic evaluation of population pharmacokinetic models for polymyxin B in patients with liver and/or kidney dysfunction. J Pharmacokinet Pharmacodyn (2024). https://doi.org/10.1007/s10928-024-09916-9

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