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External evaluation of population pharmacokinetic models for voriconazole in Chinese adult patients with hematological malignancy

  • Pharmacokinetics and Disposition
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Abstract

Objectives

Patients with hematological malignancies are prone to invasive fungal disease due to long-term chemotherapy or radiotherapy. Voriconazole is a second-generation triazole broad-spectrum antibiotic used to prevent or treat invasive fungal infections. Many population pharmacokinetic (pop PK) models have been published for voriconazole, and various diagnostic methods are available to validate the performance of these pop PK models. However, most of the published models have not been strictly evaluated externally. The purpose of this study is to evaluate these models externally and assess their predictive capabilities.

Methods

The external dataset consists of adults receiving voriconazole treatment at Fujian Medical University Union Hospital. We re-established the published models based on their final estimated values in the literature and used our external dataset for initial screening. Each model was evaluated based on the following outcomes: prediction-based diagnostics, prediction- and variability-corrected visual predictive check (pvcVPC), normalized prediction distribution errors (NPDE), and Bayesian simulation results with one to two prior observations.

Results

A total of 237 samples from 166 patients were collected as an external dataset. After screening, six candidate models suitable for the external dataset were finally obtained for comparison. Among the models, none demonstrated excellent predictive performance. Bayesian simulation shows that all models’ prediction precision and accuracy were significantly improved when one or two prior concentrations were given.

Conclusions

The published pop PK models of voriconazole have significant differences in prediction performance, and none of the models could perfectly predict the concentrations of voriconazole for our data. Therefore, extensive evaluation should precede the adoption of any model in clinical practice.

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Data availability

All data included in this study will be available upon request from the corresponding author.

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Acknowledgements

The authors thank Xiaohan Zhang (College of Arts and Sciences, University of Virginia, Charlottesville, VA, USA) for English language editing.

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Authors and Affiliations

  1. Department of Pharmacy, Fujian Medical University Union Hospital, Gulou District, 29 Xinquan Rd., Fuzhou, 350001, Fujian, China

    Weikun Huang, You Zheng, Huiping Huang, Yu Cheng, Maobai Liu & Xuemei Wu

  2. School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China

    Weikun Huang, You Zheng, Huiping Huang & Xuemei Wu

  3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA

    Nupur Chaphekar

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  1. Weikun Huang
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  2. You Zheng
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  3. Huiping Huang
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  4. Yu Cheng
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  5. Maobai Liu
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  6. Nupur Chaphekar
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  7. Xuemei Wu
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Contributions

Study design: Xuemei Wu and Weikun Huang; literature search: Weikun Huang and Yu Cheng; data collection: Weikun Huang and Maobai Liu; data analysis and plotting: Weikun Huang, You Zheng, and Huiping Huang; manuscript writing: Weikun Huang, You Zheng, and Nupur Chaphekar.

Corresponding author

Correspondence to Xuemei Wu.

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This study was performed following the Declaration of Helsinki and approved by the Ethics Committee of Fujian Medical University Union Hospital.

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The authors declare no competing interests.

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Huang, W., Zheng, Y., Huang, H. et al. External evaluation of population pharmacokinetic models for voriconazole in Chinese adult patients with hematological malignancy. Eur J Clin Pharmacol 78, 1447–1457 (2022). https://doi.org/10.1007/s00228-022-03359-2

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