CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant

Takuto Takahashi; Angela R. Smith; Pamala A. Jacobson; Abeer F. Alharbi; James Fisher; Nathan T. Rubin; Mark N. Kirstein

doi:10.5414/CP203920

CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant

Takuto Takahashi, Angela R. Smith, Pamala A. Jacobson, Abeer F. Alharbi, James Fisher, Nathan T. Rubin, Mark N. Kirstein

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a posthoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).

Original language	English (US)
Pages (from-to)	442-446
Number of pages	5
Journal	International Journal of Clinical Pharmacology and Therapeutics
Volume	59
Issue number	6
DOIs	https://doi.org/10.5414/CP203920
State	Published - Jun 2021

Bibliographical note

Funding Information:
We would like to acknowledge the assistance of the Clinical Pharmacology Shared Resource of the Masonic Cancer Center, designated by the National Cancer Institute, supported in part by P30 CA77598.

Funding Information:
This work was supported by the Hematology Oncology Pharmacist Association (HOPA) Foundation (MNK), and the Department of Pediatrics, Division of Blood and Marrow Transplant, University of Minnesota (ARS).

Publisher Copyright:
© 2021 Dustri-Verlag Dr. Karl Feistle. All rights reserved.

Keywords

CYP51A
Hepatotoxicity
Pharmacogenomics
Voriconazole

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title = "CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant",

abstract = "Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a posthoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).",

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AU - Fisher, James

AU - Rubin, Nathan T.

AU - Kirstein, Mark N.

N1 - Funding Information: We would like to acknowledge the assistance of the Clinical Pharmacology Shared Resource of the Masonic Cancer Center, designated by the National Cancer Institute, supported in part by P30 CA77598. Funding Information: This work was supported by the Hematology Oncology Pharmacist Association (HOPA) Foundation (MNK), and the Department of Pediatrics, Division of Blood and Marrow Transplant, University of Minnesota (ARS). Publisher Copyright: © 2021 Dustri-Verlag Dr. Karl Feistle. All rights reserved.

PY - 2021/6

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N2 - Fungal CYP51A (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human CYP51A1. Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a posthoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human CYP51A1 (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).

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CYP51A1 polymorphism and voriconazoleassociated hepatotoxicity in children undergoing hematopoietic cell transplant

Abstract

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