Guangting Zeng1,2, Linlin Wang1,2, Lihong Shi3, Huilan Li1,2, Miaomiao Zhu4, Jia Luo1,2, Zanling Zhang5,6. 1. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China. 2. Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. 3. Sichuan cancer hospital & institute, Chengdu, Sichuan, China. 4. Tongji Medical College, Huazhong University of Science and Technology, Wuhan Mental Health Centre; Wuhan Hospital for Psychotherapy, Wuhan, Hubei, China. 5. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China. zanlingzhang2015@126.com. 6. Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. zanlingzhang2015@126.com.
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.
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.
Authors: S Trifilio; R Ortiz; G Pennick; A Verma; J Pi; V Stosor; T Zembower; J Mehta Journal: Bone Marrow Transplant Date: 2005-03 Impact factor: 5.483
Authors: Michael J Dolton; John E Ray; Sharon C-A Chen; Kingsley Ng; Lisa G Pont; Andrew J McLachlan Journal: Antimicrob Agents Chemother Date: 2012-07-02 Impact factor: 5.191
Authors: Souzan B Yanni; Pieter P Annaert; Patrick Augustijns; Joseph G Ibrahim; Daniel K Benjamin; Dhiren R Thakker Journal: Drug Metab Dispos Date: 2010-01 Impact factor: 3.922