The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors

Youhao Chen; Yaobin Lin; Shaoxing Guan; Zerui Zhao; Daren Lin; Jin Guan; Chengzhi Zhou; Junling Liu; Xiaolong Cao; Zhichao Lin; Diyao Chen; Jianbiao Shang; Weijian Zhang; Huohui Chen; Likun Chen; Shudong Ma; Lijia Gu; Jian Zhao; Min Huang; Xueding Wang; Hao Long

doi:10.1124/dmd.123.001428

The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors

Drug Metab Dispos. 2023 Dec;51(12):1583-1590. doi: 10.1124/dmd.123.001428. Epub 2023 Sep 29.

Authors

Youhao Chen¹, Yaobin Lin¹, Shaoxing Guan¹, Zerui Zhao¹, Daren Lin¹, Jin Guan¹, Chengzhi Zhou¹, Junling Liu¹, Xiaolong Cao¹, Zhichao Lin¹, Diyao Chen¹, Jianbiao Shang¹, Weijian Zhang¹, Huohui Chen¹, Likun Chen¹, Shudong Ma¹, Lijia Gu¹, Jian Zhao¹, Min Huang², Xueding Wang², Hao Long²

Affiliations

¹ Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China (Y.C., S.G., M.H., X.W.); Departments of Thoracic Oncology (Y.L., Z.Z., H.L.) and Medical Oncology (J.L., L.C.), State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Departments of Medical Oncology (D.L.), Thoracic Surgery (Z.L.), and Gynecology (W.Z.), Jiangmen Central Hospital, Jiangmen, China; Department of Oncology, People's Hospital of Jiangmen, Jiangmen, China (J.G.); Department of Medical Pneumology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (C.Z.); Department of Medical Oncology, Guangzhou Panyu Central Hospital, Guangzhou, China (X.C.); Department of Targeted Interventional Oncology, First Hospital of Foshan, Foshan, China (D.C.); Department of Oncology, Wuyi Hospital of Traditional Chinese Medicine, Jiangmen, China (J.S.); Department of Medical Oncology, The Second People's Hospital of Zhaoqing, Zhaoqing, China (H.C.); Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China (S.M.); Department of Cardio-thoracic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (L.G.); and Department of Thoracic Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China (J.Z.).
² Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China (Y.C., S.G., M.H., X.W.); Departments of Thoracic Oncology (Y.L., Z.Z., H.L.) and Medical Oncology (J.L., L.C.), State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Departments of Medical Oncology (D.L.), Thoracic Surgery (Z.L.), and Gynecology (W.Z.), Jiangmen Central Hospital, Jiangmen, China; Department of Oncology, People's Hospital of Jiangmen, Jiangmen, China (J.G.); Department of Medical Pneumology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (C.Z.); Department of Medical Oncology, Guangzhou Panyu Central Hospital, Guangzhou, China (X.C.); Department of Targeted Interventional Oncology, First Hospital of Foshan, Foshan, China (D.C.); Department of Oncology, Wuyi Hospital of Traditional Chinese Medicine, Jiangmen, China (J.S.); Department of Medical Oncology, The Second People's Hospital of Zhaoqing, Zhaoqing, China (H.C.); Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China (S.M.); Department of Cardio-thoracic Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China (L.G.); and Department of Thoracic Surgery, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China (J.Z.) longhao@sysucc.org.cn wangxd@mail.sysu.edu.cn huangmin@mail.sysu.edu.cn.

PMID: 37775332
DOI: 10.1124/dmd.123.001428

Abstract

To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities.

Method: In this prospective study, plasma APA concentrations were quantified using liquid chromatography with tandem mass spectrometry, and 57 germline mutations were genotyped in 126 advanced solid tumor patients receiving 250 mg daily APA, a vascular endothelial growth factor receptor II inhibitor. The correlation between drug exposure, genetic factors, and the toxicity profile was analyzed.

Results: Non-small cell lung cancer (NSCLC) was more prone to APA-related toxicities and plasma concentrations of APA, and its main metabolite M1-1 could be associated with high-grade adverse events (AEs) (P < 0.01; M1-1, P < 0.01) and high-grade antiangiogenetic toxicities (APA, P = 0.034; P < 0.05), including hypertension, proteinuria, and hand-foot syndrome, in the subgroup of NSCLC. Besides, CYP2C9 rs34532201 TT carriers tended to have higher levels of APA (P < 0.001) and M1-1 (P < 0.01), whereas CYP2C9 rs1936968 GG carriers were predisposed to higher levels of M1-1 (P < 0.01).

Conclusion: Plasma APA and M1-1 exposures were able to predict severe AEs in NSCLC patients. Dose optimization and drug exposure monitoring might need consideration in NSCLC patients with CYP2C9 rs34532201 TT and rs1936968 GG.

Significance statement: Apatinib is an anti-VEGFR2 inhibitor for the treatment of multiple cancers. Though substantial in response, apatinib-induced toxicity has been a critical issue that is worth clinical surveillance. Few data on the role of drug exposure and genetic factors in apatinib-induced toxicity are available. Our study demonstrated a distinct drug-exposure relationship in NSCLC but not other tumors and provided invaluable evidence of drug exposure levels and single nucleotide polymorphisms as predictive biomarkers in apatinib-induced severe toxicities.

MeSH terms

Antineoplastic Agents* / adverse effects
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Cytochrome P-450 CYP2C9
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Polymorphism, Single Nucleotide
Prospective Studies
Vascular Endothelial Growth Factor A / therapeutic use

Substances

Antineoplastic Agents
Vascular Endothelial Growth Factor A
Cytochrome P-450 CYP2C9