Integration of genomics, clinical characteristics and baseline biological profiles to predict the risk of liver injury induced by high-dose methotrexate

Chenquan Lin; Rui Ma; Xiao Zeng; Bikui Zhang; Ting Cao; Shimeng Jiao; Hui Chen; Yifang He; Mouze Liu; Hualin Cai

doi:10.3389/fphar.2024.1423214

Integration of genomics, clinical characteristics and baseline biological profiles to predict the risk of liver injury induced by high-dose methotrexate

Front Pharmacol. 2024 Nov 28:15:1423214. doi: 10.3389/fphar.2024.1423214. eCollection 2024.

Authors

Chenquan Lin^#^{1

2

3}, Rui Ma^#^{1

2

3}, Xiao Zeng^{1

2

3}, Bikui Zhang^{1

2

3}, Ting Cao^{1

2

3}, Shimeng Jiao^{1

2

3}, Hui Chen^{1

2

3}, Yifang He^{1

2

3}, Mouze Liu^{1

2

3}, Hualin Cai^{1

2

3}

Affiliations

¹ Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.
² Institute of Clinical Pharmacy, Central South University, Changsha, China.
³ International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, Hunan, China.

^# Contributed equally.

Abstract

Background: High-dose methotrexate (HD-MTX) is commonly employed in the treatment of malignant tumors in children and young adults due to its distinctive therapeutic efficacy. Nonetheless, the systemic exposure to MTX often results in liver injury (drug induced liver injury, DILI), thereby imposing limitations on the sustained administration of HD-MTX. Additionally, individual variations including genetic underpinnings attributable to disparities in therapeutic effects and clinical toxicity remain to be elucidated.

Methods: A total of 374 patients receiving initial HD-MTX treatment were selected for this study, which aimed to establish a predictive model using binary logistic regression and a visual nomogram for DILI risk assessment. Demographic and clinical characteristics were collected at baseline and post-HD-MTX to explore their correlations with the occurrence of DILI. Additionally, genotyping of 25 single nucleotide polymorphisms from drug transporters and enzymes in the folic acid cycle was performed.

Result: G allele mutation in ABCB1 rs1128503, *1b/*1b and *1b/*15 haplotypic mutation in SLCO1B1, female gender, and MTX dosage were identified as independent factors for moderate/severe DILI. Patients with GA or AA genotype in ABCB1 rs1128503 showed significant higher 24h MTX concentration than GG, and those with *1b/*1b haplotype group in SLCO1B1 exhibited lower dose adjusted concentration (C/D) than *1a/*1a group. Besides, patient administrated with HD-MTX were more prevalent to have higher C/D levels when using intravenous plus triple intrathecal injection route than those who were using intravenous injection alone. The composite predictive model (ROC curve: AUC = 0.805), comprising above four factors and 24h MTX concentration, exhibited high accuracy.

Conclusion: Female gender, recessive mutation in ABCB1 rs1128503, and a range of MTX concentration may be risk factors for increased susceptibility to DILI. Conversely, the *1b/*1b and *1b/*15 mutations in SLCO1B1 may have a protective effect against DILI. The proposed predictive model facilitates early individual risk assessment, enabling the implementation of proactive prevention strategies.

Keywords: drug induced liver injury; methotrexate; nomogram; pharmacogenomics; therapeutic drug monitoring.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported in part by the grants from Hunan Provincial Natural Science Foundation of China (2021JJ30922), Hunan Provincial Health Commission Research Project (202113010595, W20243121), Changsha Municipal Natural Science Foundation (kq2007045), Talent Project established by Chinese Pharmaceutical Association Hospital Pharmacy Department (No. CPA-Z05-ZC-2021-003), the Fundamental Research Funds for the Central Universities of Central South University (2021zzts1073) and New Clinical Medical Technology Project of the Second Xiangya Hospital of Central South University [(2021)94].