Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study

Lijuan Zhou; Min Li; Huihong Li; Zhiqiang Guo; Yanqiu Gao; Hua Zhang; Fuli Qin; Zhihui Sang; Qinghe Xing; Long Cheng; Wei Cao

doi:10.3389/fcimb.2023.1157944

Establishment of a mathematical prediction model for voriconazole stable maintenance dose: a prospective study

Front Cell Infect Microbiol. 2023 Jul 26:13:1157944. doi: 10.3389/fcimb.2023.1157944. eCollection 2023.

Authors

Lijuan Zhou¹, Min Li¹, Huihong Li¹, Zhiqiang Guo², Yanqiu Gao³, Hua Zhang³, Fuli Qin², Zhihui Sang^{1

4}, Qinghe Xing⁵, Long Cheng⁶, Wei Cao¹

Affiliations

¹ Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China.
² Department of Hematology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China.
³ Department of Respiratory Medicine, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan, China.
⁴ College of Pharmacy, Xinxiang Medical University, Xinxiang, Henan, China.
⁵ Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China.
⁶ College of Nursing, Chifeng University, Chifeng, Inner Mongolia, China.

Abstract

Background: In patients with invasive fungal infection (IFI), the steady-state serum trough concentration (C _min) of voriconazole (VCZ) is highly variable and can lead to treatment failure (C _min < 0.5 mg/L) and toxicity (C _min ≥ 5.0 mg/L). However, It remains challenging to determine the ideal maintenance dose to achieve the desired C _min level quickly.

Aims: This randomized, prospective observational single-center study aimed to identify factors affecting VCZ-C _min and maintenance dose and create an algorithmic model to predict the necessary maintenance dose. MeThe study enrolled 306 adult IFI patients, split into two groups: non-gene-directed (A) (where CYP2C19 phenotype is not involved in determining VCZ dose) and gene-directed (B) (where CYP2C19 phenotype is involved in determining VCZ dose).

Results: Results indicated that CYP2C19 genetic polymorphisms might significantly impact VCZ loading and maintenance dose selection. CYP2C19 phenotype, C-reaction protein (CRP), and average daily dose/body weight were significant influencers on VCZ-C _min, while CYP2C19 phenotype, CRP, and body weight significantly impacted VCZ maintenance dose. A feasible predictive formula for VCZ stable maintenance dose was derived from the regression equation as a maintenance dose (mg) =282.774-0.735×age (year)+2.946×body weight(Kg)-19.402×CYP2C19 phenotype (UM/RM/NM:0, IM:1, PM:2)-0.316×CRP (mg/L) (p < 0.001).

Discussion: DiThis formula may serve as a valuable supplement to the Clinical Pharmacogenetics Implementation Consortium (CPIC^®) guideline for CYP2C19 and VCZ therapy, especially for IFI patients with highly variable inflammatory cytokines during VCZ therapy.

Keywords: CYP2C19; prediction model; proinflammatory cytokines; security; voriconazole.

Publication types

Randomized Controlled Trial
Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents* / therapeutic use
C-Reactive Protein
Cytochrome P-450 CYP2C19 / genetics
Cytochrome P-450 CYP2C19 / therapeutic use
Humans
Invasive Fungal Infections* / drug therapy
Prospective Studies
Voriconazole

Substances

Voriconazole
Antifungal Agents
Cytochrome P-450 CYP2C19
C-Reactive Protein

Grants and funding

This work was supported by the Health and Family Planning Commission of Henan Province (LHGJ20210762, LHGJ20191056), the Science and Technology Project of Henan Province (222102310224, 192102310096), Henan Educational Medicine Research Project (Wjlx2021410), and Co-construction Project of Henan Medical Science and Technology (SB201903032).