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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

  • Guangting Zeng
  • Linlin Wang
  • Lihong Shi
  • Huilan Li
  • Miaomiao Zhu
  • Jia Luo
  • Zanling ZhangEmail author
Pharmacogenetics
  • 9 Downloads

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.

Keywords

Hematological malignancies Voriconazole Loading dose Procalcitonin FMO3 POR PXR 

Notes

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.

Authors’ 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.

Funding information

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

Supplementary material

228_2020_2831_MOESM1_ESM.doc (82 kb)
ESM 1 (DOC 82 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

Authors and Affiliations

  1. 1.Department of Pharmacy, Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya HospitalCentral South UniversityChangshaChina
  3. 3.Sichuan cancer hospital & instituteChengduChina
  4. 4.Tongji Medical College, Huazhong University of Science and TechnologyWuhan Mental Health Centre; Wuhan Hospital for PsychotherapyWuhanChina

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