Variability of voriconazole concentrations in patients with hematopoietic stem cell transplantation and hematological malignancies: influence of loading dose, procalcitonin, and pregnane X receptor polymorphisms
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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.
KeywordsHematological 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.
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.
This work was supported by a grant from the Natural Science Foundation of Hunan Province (No.2017JJ2398).
- 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. https://doi.org/10.2174/1871530319666190211163245 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1002/ajh.25406 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.bbmt.2015.03.018 CrossRefGoogle Scholar
- 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. https://doi.org/10.1177/1078155218786028 CrossRefGoogle Scholar
- 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. https://doi.org/10.1128/AAC.00251-13 CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1080/00498254.2019.1672907
- 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. https://doi.org/10.1038/tpj.2015.58 CrossRefGoogle Scholar
- 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. https://doi.org/10.1016/j.ijantimicag.2019.06.026 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1093/jac/dkw349 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.jchromb.2012.12.028 CrossRefGoogle Scholar
- 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. https://doi.org/10.1124/dmd.109.029769 CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1124/dmd.116.069849 CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.11131/2015/101178