The impact of gene polymorphism and hepatic insufficiency on voriconazole dose adjustment in invasive fungal infection individuals

Guolin Li; Qinhui Li; Changji Zhang; Qin Yu; Qi Li; Xiaoshi Zhou; Rou Yang; Xuerong Yang; Hailin Liu; Yong Yang

doi:10.3389/fgene.2023.1242711

The impact of gene polymorphism and hepatic insufficiency on voriconazole dose adjustment in invasive fungal infection individuals

Front Genet. 2023 Aug 24:14:1242711. doi: 10.3389/fgene.2023.1242711. eCollection 2023.

Authors

Guolin Li^#^{1

2}, Qinhui Li^#³, Changji Zhang^{1

2}, Qin Yu⁴, Qi Li^{1

5}, Xiaoshi Zhou^{1

5}, Rou Yang^{1

5}, Xuerong Yang^{1

5}, Hailin Liu^#⁶, Yong Yang^#^{1

5}

Affiliations

¹ Department of Pharmacy, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
² School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
³ Department of Medical, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
⁴ College of Pharmacy, Southwest Medical University, Luzhou, China.
⁵ Personalized Drug Therapy Key Laboratory of Sichuan Province, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
⁶ Department of Pharmacy, The People's Hospital of Chongqing Liangjiang New Area, Chongqing, China.

^# Contributed equally.

Abstract

Voriconazole (VRZ) is a broad-spectrum antifungal medication widely used to treat invasive fungal infections (IFI). The administration dosage and blood concentration of VRZ are influenced by various factors, posing challenges for standardization and individualization of dose adjustments. On the one hand, VRZ is primarily metabolized by the liver, predominantly mediated by the cytochrome P450 (CYP) 2C19 enzyme. The genetic polymorphism of CYP2C19 significantly impacts the blood concentration of VRZ, particularly the trough concentration (Ctrough), thereby influencing the drug's efficacy and potentially causing adverse drug reactions (ADRs). Recent research has demonstrated that pharmacogenomics-based VRZ dose adjustments offer more accurate and individualized treatment strategies for individuals with hepatic insufficiency, with the possibility to enhance therapeutic outcomes and reduce ADRs. On the other hand, the security, pharmacokinetics, and dosing of VRZ in individuals with hepatic insufficiency remain unclear, making it challenging to attain optimal Ctrough in individuals with both hepatic insufficiency and IFI, resulting in suboptimal drug efficacy and severe ADRs. Therefore, when using VRZ to treat IFI, drug dosage adjustment based on individuals' genotypes and hepatic function is necessary. This review summarizes the research progress on the impact of genetic polymorphisms and hepatic insufficiency on VRZ dosage in IFI individuals, compares current international guidelines, elucidates the current application status of VRZ in individuals with hepatic insufficiency, and discusses the influence of CYP2C19, CYP3A4, CYP2C9, and ABCB1 genetic polymorphisms on VRZ dose adjustments and Ctrough at the pharmacogenomic level. Additionally, a comprehensive summary and analysis of existing studies' recommendations on VRZ dose adjustments based on CYP2C19 genetic polymorphisms and hepatic insufficiency are provided, offering a more comprehensive reference for dose selection and adjustments of VRZ in this patient population.

Keywords: CYP2C19; dose adjustment; genetic polymorphism; hepatic insufficiency; invasive fungal infections; voriconazole.

Publication types

Review

Grants and funding

This study was supported by research grants from the Chongqing Science and Health Joint Medical Research Project (No. 2022MSXM110).