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



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.


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.


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.


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.


Hematological malignancies Voriconazole Loading dose Procalcitonin FMO3 POR PXR 



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)


  1. 1.
    Sheikhbahaei S, Mohammadi A, Sherkat R, Naeini AE, Yaran M, Najafi S (2019) Invasive fungal infection in febrile patients with hematologic malignancies undergoing chemotherapy in Iran. Endocr Metab Immune Disord Drug Targets 19(3):302–307. CrossRefPubMedGoogle Scholar
  2. 2.
    Alcazer V, Conrad A, Valour F, Bachy E, Salles G, Huynh A, de Latour RP, Labussiere-Wallet H, Ader F (2019) Early-onset severe infections in allogeneic hematopoietic stem cell transplantation recipients with graft failure. Am J Hematol 94(4):E109–E111. CrossRefPubMedGoogle Scholar
  3. 3.
    Sun Y, Meng F, Han M, Zhang X, Yu L, Huang H, Wu D, Ren H, Wang C, Shen Z, Ji Y, Huang X (2015) Epidemiology, management, and outcome of invasive fungal disease in patients undergoing hematopoietic stem cell transplantation in China: a multicenter prospective observational study. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 21(6):1117–1126. CrossRefGoogle Scholar
  4. 4.
    Dolton MJ, McLachlan AJ (2014) Voriconazole pharmacokinetics and exposure-response relationships: assessing the links between exposure, efficacy and toxicity. Int J Antimicrob Ag 44(3):183–193. CrossRefGoogle Scholar
  5. 5.
    Perreault S, McManus D, Anderson A, Lin T, Ruggero M, Topal JE (2019) Evaluating a voriconazole dose modification guideline to optimize dosing in patients with hematologic malignancies. Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners 25(6):1305–1311. CrossRefGoogle Scholar
  6. 6.
    Hoenigl M, Duettmann W, Raggam RB, Seeber K, Troppan K, Fruhwald S, Prueller F, Wagner J, Valentin T, Zollner-Schwetz I, Wolfler A, Krause R (2013) Potential factors for inadequate voriconazole plasma concentrations in intensive care unit patients and patients with hematological malignancies. Antimicrob Agents Chemother 57(7):3262–3267. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Trifilio S, Ortiz R, Pennick G, Verma A, Pi J, Stosor V, Zembower T, Mehta J (2005) Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 35(5):509–513. CrossRefPubMedGoogle Scholar
  8. 8.
    Dolton MJ, Ray JE, Chen SC, Ng K, Pont LG, McLachlan AJ (2012) Multicenter study of voriconazole pharmacokinetics and therapeutic drug monitoring. Antimicrob Agents Chemother 56(9):4793–4799. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Zeng G, Shi L, Li H, Wang L, Zhu M, Luo J, Zhang Z (2019) Effect of cyclosporine a and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation. Xenobiotica; the fate of foreign compounds in biological systems:1–6.
  10. 10.
    Amsden JR, Gubbins PO (2017) Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy. Expert Opin Drug Metab Toxicol 13(11):1135–1146. CrossRefPubMedGoogle Scholar
  11. 11.
    Phillips IR, Shephard EA (2017) Drug metabolism by flavin-containing monooxygenases of human and mouse. Expert Opin Drug Metab Toxicol 13(2):167–181. CrossRefPubMedGoogle Scholar
  12. 12.
    Shirasaka Y, Chaudhry AS, McDonald M, Prasad B, Wong T, Calamia JC, Fohner A, Thornton TA, Isoherranen N, Unadkat JD, Rettie AE, Schuetz EG, Thummel KE (2016) Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content. Pharm J 16(4):375–387. CrossRefGoogle Scholar
  13. 13.
    Agrawal V, Huang N, Miller WL (2008) Pharmacogenetics of P450 oxidoreductase: effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genom 18(7):569–576. CrossRefGoogle Scholar
  14. 14.
    Harmsen S, Meijerman I, Beijnen JH, Schellens JHM (2007) The role of nuclear receptors in pharmacokinetic drug-drug interactions in oncology. Cancer Treat Rev 33(4):369–380. CrossRefPubMedGoogle Scholar
  15. 15.
    Dapia I, Garcia I, Martinez JC, Arias P, Guerra P, Diaz L, Garcia A, Ochoa D, Tenorio J, Ramirez E, Roman M, Gordo G, Saiz-Rodriguez M, Frias J, Abad-Santos F, Lapunzina P, Carcas AJ, Borobia AM (2019) Prediction models for voriconazole pharmacokinetics based on pharmacogenetics: AN exploratory study in a Spanish population. Int J Antimicrob Agents 54(4):463–470. CrossRefPubMedGoogle Scholar
  16. 16.
    Veringa A, ter Avest M, Span LFR, van den Heuvel ER, Touw DJ, Zijlstra JG, Kosterink JGW, van der Werf TS, Alffenaar JWC (2017) Voriconazole metabolism is influenced by severe inflammation: a prospective study. J Antimicrob Chemother 72(1):261–267. CrossRefPubMedGoogle Scholar
  17. 17.
    Jourdil JF, Tonini J, Stanke-Labesque F (2013) Simultaneous quantitation of azole antifungals, antibiotics, imatinib, and raltegravir in human plasma by two-dimensional high-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B 919:1–9. CrossRefGoogle Scholar
  18. 18.
    Dote S, Sawai M, Nozaki A, Naruhashi K, Kobayashi Y, Nakanishi H (2016) A retrospective analysis of patient-specific factors on voriconazole clearance. J Pharm Health Care Sci 2:10–16. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Li ZW, Peng FH, Yan M, Liang W, Liu XL, Wu YQ, Lin XB, Tan SL, Wang F, Xu P, Fang PF, Liu YP, Xiang DX, Zhang BK (2017) Impact of CYP2C19 genotype and liver function on voriconazole pharmacokinetics in renal transplant recipients. Ther Drug Monit 39(4):422–428CrossRefGoogle Scholar
  20. 20.
    Morgan ET (2009) Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther 85(4):434–438. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Redl H, Schiesser A, Togel E, Assicot M, Bohuon C (2001) Possible role of TNF on procalcitonin release in a baboon model of sepsis. Shock 16(1):25–27. CrossRefPubMedGoogle Scholar
  22. 22.
    Shah RR, Smith RL (2015) Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos 43(3):400–410. CrossRefPubMedGoogle Scholar
  23. 23.
    Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK, Thakker DR (2010) In vitro hepatic metabolism explains higher clearance of Voriconazole in children versus adults: role of CYP2C19 and flavin-containing monooxygenase 3. Drug Metab Dispos 38(1):25–31. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhang HF, Li ZH, Liu JY, Liu TT, Wang P, Fang Y, Zhou J, Cui MZ, Gao N, Tian X, Gao J, Wen Q, Jia LJ, Qiao HL (2016) Correlation of cytochrome P450 oxidoreductase expression with the expression of 10 isoforms of cytochrome P450 in human liver. Drug Metab Dispos 44(8):1193–1200. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Mbatchi LC, Brouillet JP, Evrard A (2018) Genetic variations of the xenoreceptors NR1I2 and NR1I3 and their effect on drug disposition and response variability. Pharmacogenomics 19(1):61–77. CrossRefPubMedGoogle Scholar
  26. 26.
    Prakash C, Zuniga B, Song CS, Jiang S, Cropper J, Park S, Chatterjee B (2015) Nuclear receptors in drug metabolism, drug response and drug interactions. Nuclear Receptor Res 2.

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

Personalised recommendations