The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors
Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:51 |
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| Enthalten in: |
Drug metabolism and disposition: the biological fate of chemicals - 51(2023), 12 vom: 29. Dez., Seite 1583-1590 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Youhao [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 16.11.2023 Date Revised 29.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1124/dmd.123.001428 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM362714061 |
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| 245 | 1 | 4 | |a The Effects of Drug Exposure and Single Nucleotide Polymorphisms on Aaptinib-Induced Severe Toxicities in Solid Tumors |
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| 500 | |a Date Completed 16.11.2023 | ||
| 500 | |a Date Revised 29.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics. | ||
| 520 | |a To investigate the value of drug exposure and host germline genetic factors in predicting apatinib (APA)-related toxicities | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
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| 700 | 1 | |a Zhao, Zerui |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Daren |e verfasserin |4 aut | |
| 700 | 1 | |a Guan, Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Chengzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Junling |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Xiaolong |e verfasserin |4 aut | |
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| 700 | 1 | |a Shang, Jianbiao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Weijian |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Huohui |e verfasserin |4 aut | |
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| 700 | 1 | |a Wang, Xueding |e verfasserin |4 aut | |
| 700 | 1 | |a Long, Hao |e verfasserin |4 aut | |
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