Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity
Background Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib. Objective To assess the frequency, degree, and onset of international normalized ratio el...
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| Veröffentlicht in: | Journal of oncology pharmacy practice 2019-10, Vol.25 (7), p.1599-1607 |
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| container_title | Journal of oncology pharmacy practice |
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| creator | Hiraide, Makoto Minowa, Yuichi Nakano, Yasuhiro Suzuki, Kenichi Shiga, Taro Nishio, Makoto Miyoshi, Junya Takahashi, Harumi Hama, Toshihiro |
| description | Background
Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib.
Objective
To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity.
Methods
This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study.
Results
Compared with international normalized ratio at the baseline significant (P |
| doi_str_mv | 10.1177/1078155218801061 |
| format | Article |
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Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib.
Objective
To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity.
Methods
This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study.
Results
Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing.
Conclusion
In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.</description><identifier>ISSN: 1078-1552</identifier><identifier>EISSN: 1477-092X</identifier><identifier>DOI: 10.1177/1078155218801061</identifier><identifier>PMID: 30253730</identifier><language>eng</language><publisher>London, England: SAGE Publications</publisher><subject>Anticoagulants ; Complications ; Cytochrome ; Cytochrome P450 ; Enzyme inhibitors ; Gefitinib ; Hydroxylation ; Inhibitor drugs ; Inhibitors ; International standards ; Plasma levels ; Targeted cancer therapy ; Tyrosine kinase inhibitors ; Warfarin</subject><ispartof>Journal of oncology pharmacy practice, 2019-10, Vol.25 (7), p.1599-1607</ispartof><rights>The Author(s) 2018</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c431t-1761accb7045a0485fa4c9aa3cc2b2850caa23ae34e93a38ee35db2c09a04eef3</citedby><cites>FETCH-LOGICAL-c431t-1761accb7045a0485fa4c9aa3cc2b2850caa23ae34e93a38ee35db2c09a04eef3</cites><orcidid>0000-0002-5243-9926</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/1078155218801061$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/1078155218801061$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>315,781,785,21823,27928,27929,43625,43626</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30253730$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hiraide, Makoto</creatorcontrib><creatorcontrib>Minowa, Yuichi</creatorcontrib><creatorcontrib>Nakano, Yasuhiro</creatorcontrib><creatorcontrib>Suzuki, Kenichi</creatorcontrib><creatorcontrib>Shiga, Taro</creatorcontrib><creatorcontrib>Nishio, Makoto</creatorcontrib><creatorcontrib>Miyoshi, Junya</creatorcontrib><creatorcontrib>Takahashi, Harumi</creatorcontrib><creatorcontrib>Hama, Toshihiro</creatorcontrib><title>Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity</title><title>Journal of oncology pharmacy practice</title><addtitle>J Oncol Pharm Pract</addtitle><description>Background
Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib.
Objective
To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity.
Methods
This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study.
Results
Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing.
Conclusion
In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.</description><subject>Anticoagulants</subject><subject>Complications</subject><subject>Cytochrome</subject><subject>Cytochrome P450</subject><subject>Enzyme inhibitors</subject><subject>Gefitinib</subject><subject>Hydroxylation</subject><subject>Inhibitor drugs</subject><subject>Inhibitors</subject><subject>International standards</subject><subject>Plasma levels</subject><subject>Targeted cancer therapy</subject><subject>Tyrosine kinase inhibitors</subject><subject>Warfarin</subject><issn>1078-1552</issn><issn>1477-092X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp1UcFu1DAQjRCIlsKdE7LEBQ5px3a8drhVC4VKleAAEpyiiXeydcnare1ttXxNfwW-rM5uAQmJkz3z3rw39quq5xwOOdf6iIM2XCnBjQEOM_6g2ueN1jW04uvDci9wPeF71ZOULgDAaGEeV3sShJJawn71821cL5nzmSLa7IJPrKd8Q-RZ3sSQnCf23XlMVEjnrnc5xMReLWlw2XnXM_QLRnEM2-r1trzBOGB0_g07TolSWpHPLAw7F4-TC47Mh7jC0f2gBYtTj9FI11uQ2XOctqHoUnY2bUWd_3V77XIMbP7tk5i3bFq3NDZPq0cDjome3Z8H1ZeTd5_nH-qzj-9P58dntW0kzzXXM47W9hoahdAYNWBjW0RpreiFUWARhUSSDbUSpSGSatELC21hEw3yoHq5072M4WpNKXcXYV2eM6ZOCMNBKQ2zwoIdy5bPS5GG7jK6FcZNx6GbMuv-zayMvLgXXvcrWvwZ-B1SIdQ7QsIl_XX9r-AddROksw</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Hiraide, Makoto</creator><creator>Minowa, Yuichi</creator><creator>Nakano, Yasuhiro</creator><creator>Suzuki, Kenichi</creator><creator>Shiga, Taro</creator><creator>Nishio, Makoto</creator><creator>Miyoshi, Junya</creator><creator>Takahashi, Harumi</creator><creator>Hama, Toshihiro</creator><general>SAGE Publications</general><general>Sage Publications Ltd</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TO</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><orcidid>https://orcid.org/0000-0002-5243-9926</orcidid></search><sort><creationdate>20191001</creationdate><title>Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity</title><author>Hiraide, Makoto ; Minowa, Yuichi ; Nakano, Yasuhiro ; Suzuki, Kenichi ; Shiga, Taro ; Nishio, Makoto ; Miyoshi, Junya ; Takahashi, Harumi ; Hama, Toshihiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c431t-1761accb7045a0485fa4c9aa3cc2b2850caa23ae34e93a38ee35db2c09a04eef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Anticoagulants</topic><topic>Complications</topic><topic>Cytochrome</topic><topic>Cytochrome P450</topic><topic>Enzyme inhibitors</topic><topic>Gefitinib</topic><topic>Hydroxylation</topic><topic>Inhibitor drugs</topic><topic>Inhibitors</topic><topic>International standards</topic><topic>Plasma levels</topic><topic>Targeted cancer therapy</topic><topic>Tyrosine kinase inhibitors</topic><topic>Warfarin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hiraide, Makoto</creatorcontrib><creatorcontrib>Minowa, Yuichi</creatorcontrib><creatorcontrib>Nakano, Yasuhiro</creatorcontrib><creatorcontrib>Suzuki, Kenichi</creatorcontrib><creatorcontrib>Shiga, Taro</creatorcontrib><creatorcontrib>Nishio, Makoto</creatorcontrib><creatorcontrib>Miyoshi, Junya</creatorcontrib><creatorcontrib>Takahashi, Harumi</creatorcontrib><creatorcontrib>Hama, Toshihiro</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Journal of oncology pharmacy practice</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hiraide, Makoto</au><au>Minowa, Yuichi</au><au>Nakano, Yasuhiro</au><au>Suzuki, Kenichi</au><au>Shiga, Taro</au><au>Nishio, Makoto</au><au>Miyoshi, Junya</au><au>Takahashi, Harumi</au><au>Hama, Toshihiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity</atitle><jtitle>Journal of oncology pharmacy practice</jtitle><addtitle>J Oncol Pharm Pract</addtitle><date>2019-10-01</date><risdate>2019</risdate><volume>25</volume><issue>7</issue><spage>1599</spage><epage>1607</epage><pages>1599-1607</pages><issn>1078-1552</issn><eissn>1477-092X</eissn><abstract>Background
Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib.
Objective
To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity.
Methods
This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study.
Results
Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing.
Conclusion
In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.</abstract><cop>London, England</cop><pub>SAGE Publications</pub><pmid>30253730</pmid><doi>10.1177/1078155218801061</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-5243-9926</orcidid></addata></record> |
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| language | eng |
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| subjects | Anticoagulants Complications Cytochrome Cytochrome P450 Enzyme inhibitors Gefitinib Hydroxylation Inhibitor drugs Inhibitors International standards Plasma levels Targeted cancer therapy Tyrosine kinase inhibitors Warfarin |
| title | Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity |
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