Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers

Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations ( C trough ) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated...

Full description

Saved in:
Bibliographic Details
Published in:Cancer chemotherapy and pharmacology 2021-06, Vol.87 (6), p.767-777
Main Authors: Kobayashi, Kazuo, Sugiyama, Erika, Shinozaki, Eiji, Wakatsuki, Takeru, Tajima, Masataka, Kidokoro, Hiyori, Aoyama, Takeshi, Nakano, Yasuhiro, Kawakami, Kazuyoshi, Hashimoto, Koki, Suenaga, Mitsukuni, Ichimura, Takashi, Ogura, Mariko, Chin, Keisho, Nakayama, Izuma, Ooki, Akira, Takahari, Daisuke, Suzuki, Wataru, Yokokawa, Takashi, Minowa, Yuichi, Hiraoka, Tomoko, Suzuki, Kenichi, Sato, Hitoshi, Hama, Toshihiro, Yamaguchi, Kensei
Format: Article
Language:English
Subjects:
Bilirubin
Cancer
Cancer Research
Colorectal cancer
Colorectal carcinoma
Enzyme inhibitors
Evaluation
Exanthema
Gene polymorphism
Hypertension
Kinases
Medicine
Medicine & Public Health
Metabolites
Metastases
Metastasis
Multivariate analysis
Oncology
Original Article
Pharmacodynamics
Pharmacokinetics
Pharmacology
Pharmacology/Toxicology
Protein-tyrosine kinase
Targeted cancer therapy
Tyrosine
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
cited_by cdi_FETCH-LOGICAL-c430t-3f014e322cfc568fb465685fbc20f12d5211fcca0309b77a6a551f29479752db3
cites cdi_FETCH-LOGICAL-c430t-3f014e322cfc568fb465685fbc20f12d5211fcca0309b77a6a551f29479752db3
container_end_page 777
container_issue 6
container_start_page 767
container_title Cancer chemotherapy and pharmacology
container_volume 87
creator Kobayashi, Kazuo
Sugiyama, Erika
Shinozaki, Eiji
Wakatsuki, Takeru
Tajima, Masataka
Kidokoro, Hiyori
Aoyama, Takeshi
Nakano, Yasuhiro
Kawakami, Kazuyoshi
Hashimoto, Koki
Suenaga, Mitsukuni
Ichimura, Takashi
Ogura, Mariko
Chin, Keisho
Nakayama, Izuma
Ooki, Akira
Takahari, Daisuke
Suzuki, Wataru
Yokokawa, Takashi
Minowa, Yuichi
Hiraoka, Tomoko
Suzuki, Kenichi
Sato, Hitoshi
Hama, Toshihiro
Yamaguchi, Kensei
description Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations ( C trough ) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. Methods The C trough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2 , SLCO1B1 , and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. Results We analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the C trough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 ( p  = 0.010). The M5 C trough levels were significantly associated with the severity of hypertension or rash ( p  
doi_str_mv 10.1007/s00280-021-04237-x
format article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2524567965</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2524567965</sourcerecordid><originalsourceid>FETCH-LOGICAL-c430t-3f014e322cfc568fb465685fbc20f12d5211fcca0309b77a6a551f29479752db3</originalsourceid><addsrcrecordid>eNp9kc1uFDEQhC0EIpvAC3BAlrgy0P6b2TkuK0iQInGBs-Xx2BtHM_bg9ubneXhRvNkFbpxadn9V1VIR8obBBwbQfUQAvoYGOGtActE1D8_IiknBG1hL8ZysQEjZqA7kGTlHvAUAyYR4Sc6EaIUSPV-RXxvEZIMpIUWkZk5xR5fJ4GyoTdG6WPJplzzNbpey8S6GgZo40lCQzq6YIU2hOHxPzXjnMjrq7qrw8K7Q5tP2ktMlTY9zystNwBlpiHSptgeI3ody8-SCpX7ZGjul7GwxE7WmXpDxFXnhzYTu9WlekB9fPn_fXjXX3y6_bjfXjZUCSiM8MOkE59Zb1a79INs6lB8sB8_4qDhj3loDAvqh60xrlGKe97LrO8XHQVyQd0ffJaefe4dF36Z9jjVSc8Wlaru-VZXiR8rmhJid10sOs8mPmoE-9KKPvejai37qRT9U0duT9X6Y3fhX8qeICogjgHUVdy7_y_6P7W_gEZxU</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2524567965</pqid></control><display><type>article</type><title>Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers</title><source>Springer Link</source><creator>Kobayashi, Kazuo ; Sugiyama, Erika ; Shinozaki, Eiji ; Wakatsuki, Takeru ; Tajima, Masataka ; Kidokoro, Hiyori ; Aoyama, Takeshi ; Nakano, Yasuhiro ; Kawakami, Kazuyoshi ; Hashimoto, Koki ; Suenaga, Mitsukuni ; Ichimura, Takashi ; Ogura, Mariko ; Chin, Keisho ; Nakayama, Izuma ; Ooki, Akira ; Takahari, Daisuke ; Suzuki, Wataru ; Yokokawa, Takashi ; Minowa, Yuichi ; Hiraoka, Tomoko ; Suzuki, Kenichi ; Sato, Hitoshi ; Hama, Toshihiro ; Yamaguchi, Kensei</creator><creatorcontrib>Kobayashi, Kazuo ; Sugiyama, Erika ; Shinozaki, Eiji ; Wakatsuki, Takeru ; Tajima, Masataka ; Kidokoro, Hiyori ; Aoyama, Takeshi ; Nakano, Yasuhiro ; Kawakami, Kazuyoshi ; Hashimoto, Koki ; Suenaga, Mitsukuni ; Ichimura, Takashi ; Ogura, Mariko ; Chin, Keisho ; Nakayama, Izuma ; Ooki, Akira ; Takahari, Daisuke ; Suzuki, Wataru ; Yokokawa, Takashi ; Minowa, Yuichi ; Hiraoka, Tomoko ; Suzuki, Kenichi ; Sato, Hitoshi ; Hama, Toshihiro ; Yamaguchi, Kensei</creatorcontrib><description>Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations ( C trough ) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. Methods The C trough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2 , SLCO1B1 , and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. Results We analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the C trough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 ( p  = 0.010). The M5 C trough levels were significantly associated with the severity of hypertension or rash ( p  &lt; 0.05). In a multivariate analysis, the M5 C trough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms ( p  = 0.035). Conclusion This study showed that the C trough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the C trough of M5 was significantly correlated with hypertension and severe rash.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-021-04237-x</identifier><identifier>PMID: 33635392</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Bilirubin ; Cancer ; Cancer Research ; Colorectal cancer ; Colorectal carcinoma ; Enzyme inhibitors ; Evaluation ; Exanthema ; Gene polymorphism ; Hypertension ; Kinases ; Medicine ; Medicine &amp; Public Health ; Metabolites ; Metastases ; Metastasis ; Multivariate analysis ; Oncology ; Original Article ; Pharmacodynamics ; Pharmacokinetics ; Pharmacology ; Pharmacology/Toxicology ; Protein-tyrosine kinase ; Targeted cancer therapy ; Tyrosine</subject><ispartof>Cancer chemotherapy and pharmacology, 2021-06, Vol.87 (6), p.767-777</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021</rights><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-3f014e322cfc568fb465685fbc20f12d5211fcca0309b77a6a551f29479752db3</citedby><cites>FETCH-LOGICAL-c430t-3f014e322cfc568fb465685fbc20f12d5211fcca0309b77a6a551f29479752db3</cites><orcidid>0000-0001-9988-128X ; 0000-0003-2023-1300 ; 0000-0002-0767-2606 ; 0000-0002-9615-0489</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33635392$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kobayashi, Kazuo</creatorcontrib><creatorcontrib>Sugiyama, Erika</creatorcontrib><creatorcontrib>Shinozaki, Eiji</creatorcontrib><creatorcontrib>Wakatsuki, Takeru</creatorcontrib><creatorcontrib>Tajima, Masataka</creatorcontrib><creatorcontrib>Kidokoro, Hiyori</creatorcontrib><creatorcontrib>Aoyama, Takeshi</creatorcontrib><creatorcontrib>Nakano, Yasuhiro</creatorcontrib><creatorcontrib>Kawakami, Kazuyoshi</creatorcontrib><creatorcontrib>Hashimoto, Koki</creatorcontrib><creatorcontrib>Suenaga, Mitsukuni</creatorcontrib><creatorcontrib>Ichimura, Takashi</creatorcontrib><creatorcontrib>Ogura, Mariko</creatorcontrib><creatorcontrib>Chin, Keisho</creatorcontrib><creatorcontrib>Nakayama, Izuma</creatorcontrib><creatorcontrib>Ooki, Akira</creatorcontrib><creatorcontrib>Takahari, Daisuke</creatorcontrib><creatorcontrib>Suzuki, Wataru</creatorcontrib><creatorcontrib>Yokokawa, Takashi</creatorcontrib><creatorcontrib>Minowa, Yuichi</creatorcontrib><creatorcontrib>Hiraoka, Tomoko</creatorcontrib><creatorcontrib>Suzuki, Kenichi</creatorcontrib><creatorcontrib>Sato, Hitoshi</creatorcontrib><creatorcontrib>Hama, Toshihiro</creatorcontrib><creatorcontrib>Yamaguchi, Kensei</creatorcontrib><title>Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations ( C trough ) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. Methods The C trough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2 , SLCO1B1 , and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. Results We analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the C trough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 ( p  = 0.010). The M5 C trough levels were significantly associated with the severity of hypertension or rash ( p  &lt; 0.05). In a multivariate analysis, the M5 C trough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms ( p  = 0.035). Conclusion This study showed that the C trough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the C trough of M5 was significantly correlated with hypertension and severe rash.</description><subject>Bilirubin</subject><subject>Cancer</subject><subject>Cancer Research</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Enzyme inhibitors</subject><subject>Evaluation</subject><subject>Exanthema</subject><subject>Gene polymorphism</subject><subject>Hypertension</subject><subject>Kinases</subject><subject>Medicine</subject><subject>Medicine &amp; Public Health</subject><subject>Metabolites</subject><subject>Metastases</subject><subject>Metastasis</subject><subject>Multivariate analysis</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Pharmacology/Toxicology</subject><subject>Protein-tyrosine kinase</subject><subject>Targeted cancer therapy</subject><subject>Tyrosine</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kc1uFDEQhC0EIpvAC3BAlrgy0P6b2TkuK0iQInGBs-Xx2BtHM_bg9ubneXhRvNkFbpxadn9V1VIR8obBBwbQfUQAvoYGOGtActE1D8_IiknBG1hL8ZysQEjZqA7kGTlHvAUAyYR4Sc6EaIUSPV-RXxvEZIMpIUWkZk5xR5fJ4GyoTdG6WPJplzzNbpey8S6GgZo40lCQzq6YIU2hOHxPzXjnMjrq7qrw8K7Q5tP2ktMlTY9zystNwBlpiHSptgeI3ody8-SCpX7ZGjul7GwxE7WmXpDxFXnhzYTu9WlekB9fPn_fXjXX3y6_bjfXjZUCSiM8MOkE59Zb1a79INs6lB8sB8_4qDhj3loDAvqh60xrlGKe97LrO8XHQVyQd0ffJaefe4dF36Z9jjVSc8Wlaru-VZXiR8rmhJid10sOs8mPmoE-9KKPvejai37qRT9U0duT9X6Y3fhX8qeICogjgHUVdy7_y_6P7W_gEZxU</recordid><startdate>20210601</startdate><enddate>20210601</enddate><creator>Kobayashi, Kazuo</creator><creator>Sugiyama, Erika</creator><creator>Shinozaki, Eiji</creator><creator>Wakatsuki, Takeru</creator><creator>Tajima, Masataka</creator><creator>Kidokoro, Hiyori</creator><creator>Aoyama, Takeshi</creator><creator>Nakano, Yasuhiro</creator><creator>Kawakami, Kazuyoshi</creator><creator>Hashimoto, Koki</creator><creator>Suenaga, Mitsukuni</creator><creator>Ichimura, Takashi</creator><creator>Ogura, Mariko</creator><creator>Chin, Keisho</creator><creator>Nakayama, Izuma</creator><creator>Ooki, Akira</creator><creator>Takahari, Daisuke</creator><creator>Suzuki, Wataru</creator><creator>Yokokawa, Takashi</creator><creator>Minowa, Yuichi</creator><creator>Hiraoka, Tomoko</creator><creator>Suzuki, Kenichi</creator><creator>Sato, Hitoshi</creator><creator>Hama, Toshihiro</creator><creator>Yamaguchi, Kensei</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><orcidid>https://orcid.org/0000-0001-9988-128X</orcidid><orcidid>https://orcid.org/0000-0003-2023-1300</orcidid><orcidid>https://orcid.org/0000-0002-0767-2606</orcidid><orcidid>https://orcid.org/0000-0002-9615-0489</orcidid></search><sort><creationdate>20210601</creationdate><title>Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers</title><author>Kobayashi, Kazuo ; Sugiyama, Erika ; Shinozaki, Eiji ; Wakatsuki, Takeru ; Tajima, Masataka ; Kidokoro, Hiyori ; Aoyama, Takeshi ; Nakano, Yasuhiro ; Kawakami, Kazuyoshi ; Hashimoto, Koki ; Suenaga, Mitsukuni ; Ichimura, Takashi ; Ogura, Mariko ; Chin, Keisho ; Nakayama, Izuma ; Ooki, Akira ; Takahari, Daisuke ; Suzuki, Wataru ; Yokokawa, Takashi ; Minowa, Yuichi ; Hiraoka, Tomoko ; Suzuki, Kenichi ; Sato, Hitoshi ; Hama, Toshihiro ; Yamaguchi, Kensei</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-3f014e322cfc568fb465685fbc20f12d5211fcca0309b77a6a551f29479752db3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Bilirubin</topic><topic>Cancer</topic><topic>Cancer Research</topic><topic>Colorectal cancer</topic><topic>Colorectal carcinoma</topic><topic>Enzyme inhibitors</topic><topic>Evaluation</topic><topic>Exanthema</topic><topic>Gene polymorphism</topic><topic>Hypertension</topic><topic>Kinases</topic><topic>Medicine</topic><topic>Medicine &amp; Public Health</topic><topic>Metabolites</topic><topic>Metastases</topic><topic>Metastasis</topic><topic>Multivariate analysis</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pharmacodynamics</topic><topic>Pharmacokinetics</topic><topic>Pharmacology</topic><topic>Pharmacology/Toxicology</topic><topic>Protein-tyrosine kinase</topic><topic>Targeted cancer therapy</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kobayashi, Kazuo</creatorcontrib><creatorcontrib>Sugiyama, Erika</creatorcontrib><creatorcontrib>Shinozaki, Eiji</creatorcontrib><creatorcontrib>Wakatsuki, Takeru</creatorcontrib><creatorcontrib>Tajima, Masataka</creatorcontrib><creatorcontrib>Kidokoro, Hiyori</creatorcontrib><creatorcontrib>Aoyama, Takeshi</creatorcontrib><creatorcontrib>Nakano, Yasuhiro</creatorcontrib><creatorcontrib>Kawakami, Kazuyoshi</creatorcontrib><creatorcontrib>Hashimoto, Koki</creatorcontrib><creatorcontrib>Suenaga, Mitsukuni</creatorcontrib><creatorcontrib>Ichimura, Takashi</creatorcontrib><creatorcontrib>Ogura, Mariko</creatorcontrib><creatorcontrib>Chin, Keisho</creatorcontrib><creatorcontrib>Nakayama, Izuma</creatorcontrib><creatorcontrib>Ooki, Akira</creatorcontrib><creatorcontrib>Takahari, Daisuke</creatorcontrib><creatorcontrib>Suzuki, Wataru</creatorcontrib><creatorcontrib>Yokokawa, Takashi</creatorcontrib><creatorcontrib>Minowa, Yuichi</creatorcontrib><creatorcontrib>Hiraoka, Tomoko</creatorcontrib><creatorcontrib>Suzuki, Kenichi</creatorcontrib><creatorcontrib>Sato, Hitoshi</creatorcontrib><creatorcontrib>Hama, Toshihiro</creatorcontrib><creatorcontrib>Yamaguchi, Kensei</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health &amp; Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health &amp; Medical Complete (Alumni)</collection><collection>Health &amp; Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kobayashi, Kazuo</au><au>Sugiyama, Erika</au><au>Shinozaki, Eiji</au><au>Wakatsuki, Takeru</au><au>Tajima, Masataka</au><au>Kidokoro, Hiyori</au><au>Aoyama, Takeshi</au><au>Nakano, Yasuhiro</au><au>Kawakami, Kazuyoshi</au><au>Hashimoto, Koki</au><au>Suenaga, Mitsukuni</au><au>Ichimura, Takashi</au><au>Ogura, Mariko</au><au>Chin, Keisho</au><au>Nakayama, Izuma</au><au>Ooki, Akira</au><au>Takahari, Daisuke</au><au>Suzuki, Wataru</au><au>Yokokawa, Takashi</au><au>Minowa, Yuichi</au><au>Hiraoka, Tomoko</au><au>Suzuki, Kenichi</au><au>Sato, Hitoshi</au><au>Hama, Toshihiro</au><au>Yamaguchi, Kensei</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2021-06-01</date><risdate>2021</risdate><volume>87</volume><issue>6</issue><spage>767</spage><epage>777</epage><pages>767-777</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><abstract>Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations ( C trough ) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. Methods The C trough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2 , SLCO1B1 , and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. Results We analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the C trough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 ( p  = 0.010). The M5 C trough levels were significantly associated with the severity of hypertension or rash ( p  &lt; 0.05). In a multivariate analysis, the M5 C trough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms ( p  = 0.035). Conclusion This study showed that the C trough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the C trough of M5 was significantly correlated with hypertension and severe rash.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>33635392</pmid><doi>10.1007/s00280-021-04237-x</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-9988-128X</orcidid><orcidid>https://orcid.org/0000-0003-2023-1300</orcidid><orcidid>https://orcid.org/0000-0002-0767-2606</orcidid><orcidid>https://orcid.org/0000-0002-9615-0489</orcidid></addata></record>
fulltext fulltext
identifier ISSN: 0344-5704
ispartof Cancer chemotherapy and pharmacology, 2021-06, Vol.87 (6), p.767-777
issn 0344-5704
1432-0843
language eng
recordid cdi_proquest_journals_2524567965
source Springer Link
subjects Bilirubin
Cancer
Cancer Research
Colorectal cancer
Colorectal carcinoma
Enzyme inhibitors
Evaluation
Exanthema
Gene polymorphism
Hypertension
Kinases
Medicine
Medicine & Public Health
Metabolites
Metastases
Metastasis
Multivariate analysis
Oncology
Original Article
Pharmacodynamics
Pharmacokinetics
Pharmacology
Pharmacology/Toxicology
Protein-tyrosine kinase
Targeted cancer therapy
Tyrosine
title Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-09-22T03%3A34%3A50IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Associations%20among%20plasma%20concentrations%20of%20regorafenib%20and%20its%20metabolites,%20adverse%20events,%20and%20ABCG2%20polymorphisms%20in%20patients%20with%20metastatic%20colorectal%20cancers&rft.jtitle=Cancer%20chemotherapy%20and%20pharmacology&rft.au=Kobayashi,%20Kazuo&rft.date=2021-06-01&rft.volume=87&rft.issue=6&rft.spage=767&rft.epage=777&rft.pages=767-777&rft.issn=0344-5704&rft.eissn=1432-0843&rft_id=info:doi/10.1007/s00280-021-04237-x&rft_dat=%3Cproquest_cross%3E2524567965%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c430t-3f014e322cfc568fb465685fbc20f12d5211fcca0309b77a6a551f29479752db3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2524567965&rft_id=info:pmid/33635392&rfr_iscdi=true