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Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies: influence of loading dose, procalcitonin, and pregnane X receptor polymorphisms

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Aims

Voriconazole (VCZ) displays highly variable pharmacokinetics affecting treatment efficacy and safety. We aimed to identify the factors affecting VCZ steady-state trough concentration (Cssmin) to provide evidence for optimizing VCZ treatment regimens.

Methods

A total of 510 Cssmin of 172 patients with hematopoietic stem cell transplantation and hematologic malignancies and their clinical characteristics and genotypes of FMO, POR, and PXR were included in this study.

Results

In univariate analysis, the standard loading dose of VCZ significantly increased the Cssmin of VCZ (P < 0.001). The Cssmin of VCZ was significantly correlated with patients’ total bilirubin (TB) (P < 0.001) and procalcitonin (PCT) (P < 0.001). FMO3 rs2266780 (P = 0.025), POR rs10954732 (P = 0.015), PXR rs2461817 (P = 0.010), PXR rs7643645 (P = 0.003), PXR rs3732359 (P = 0.014), PXR rs3814057 (P = 0.005), and PXR rs6785049 (P = 0.013) have a significant effect on Cssmin of VCZ. Loading dose, TB, PCT level, and PXRrs3814057 polymorphism were independent influencing factors of VCZ Cssmin in the analysis of multivariate linear regression. And loading dose, PCT, and PXR rs3814057 had significant effects on the probability of the therapeutic window of VCZ.

Conclusion

The high variability of VCZ Cssmin may be partially explained by loading dose, liver function, inflammation, and PXR polymorphisms. This study suggests the VCZ standard loading dose regimen significantly increased Cssmin and probability of the therapeutic window providing treatment benefits. Patients in the high PCT group may be more likely to exceed 5.5 μg/mL, thus suffering from VCZ toxicity.

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Acknowledgments

We thank all patients who contributed to this work. We thank Professor Shusen Sun from College of Pharmacy and Health Science at Western New England University, USA, for his valuable advice.

Funding

This work was supported by a grant from the Natural Science Foundation of Hunan Province (No.2017JJ2398).

Author information

Author notes

  1. Guangting Zeng and Linlin Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Guangting Zeng, Linlin Wang, Huilan Li, Jia Luo & Zanling Zhang

  2. Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China

    Guangting Zeng, Linlin Wang, Huilan Li, Jia Luo & Zanling Zhang

  3. Sichuan cancer hospital & institute, Chengdu, Sichuan, China

    Lihong Shi

  4. Tongji Medical College, Huazhong University of Science and Technology, Wuhan Mental Health Centre; Wuhan Hospital for Psychotherapy, Wuhan, Hubei, China

    Miaomiao Zhu

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  1. Guangting Zeng
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Contributions

Zanling Zhang and Jia Luo designed the study. Guangting Zeng and Linlin Wang performed the date analysis and wrote the manuscript. Lihong Shi and Huilan Li recuited patients. Miaomiao Zhu extracted the DNA.

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Correspondence to Zanling Zhang.

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Zeng, G., Wang, L., Shi, L. et al. Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies: influence of loading dose, procalcitonin, and pregnane X receptor polymorphisms. Eur J Clin Pharmacol 76, 515–523 (2020). https://doi.org/10.1007/s00228-020-02831-1

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