Pazopanib exposure decreases as a result of an ifosfamide-dependent drug–drug interaction: results of a phase I study
Background: The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1–3, has activity as single agent and is attractive to enhance anti-tumour...
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| Veröffentlicht in: | British journal of cancer 2014-02, Vol.110 (4), p.888-893 |
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| creator | Hamberg, P Boers-Sonderen, M J van der Graaf, W T A de Bruijn, P Suttle, A B Eskens, F A L M Verweij, J van Herpen, C M L Sleijfer, S |
| description | Background:
The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1–3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.
Methods:
In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m
−2
per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.
Results:
Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.
Conclusion:
Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m
−2
per cycle, every 3 weeks) is 800 mg daily. |
| doi_str_mv | 10.1038/bjc.2013.798 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3929878</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3222400501</sourcerecordid><originalsourceid>FETCH-LOGICAL-c480t-e8dd8bea01a90bd1737bae7aee4175819d8f16d569b2b3e44f3da134d6c6775e3</originalsourceid><addsrcrecordid>eNptkU1rFEEQhhtRzBq9eZYG8eZs-mOmPzwIEjQGAvGg56ZmumYzy2732D2jxpP_wX_oL0mvu8YIQkFR1FNvvfAS8pSzJWfSnLTrbikYl0ttzT2y4I0UFTdC3ycLxpiumBXsiDzKeV1Gy4x-SI5ELZUSVi_I1w_wPY4QhpbitzHmOSH12CWEjJlCKZowz5uJxp5CoEMfcw_bwWPlccTgMUzUp3n168fPXaNDmDBBNw0xvDqc5t-3dLwqmvSc5mn214_Jgx42GZ8c-jH59O7tx9P31cXl2fnpm4uqqw2bKjTemxaBcbCs9VxL3QJqQKy5bgy33vRc-UbZVrQS67qXHrisveqU1g3KY_J6rzvO7RZ9V-wm2LgxDVtI1y7C4P7dhOHKreIXJ62wRpsi8PwgkOLnGfPk1nFOoXh2vLZWSaFqWaiXe6pLMeeE_e0HztwuJldicruYXImp4M_uurqF_-RSgBcHAHIHmz5B6Ib8lzOCK9OwwlV7LpdVWGG64-5_j28AnHKtwg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1499632643</pqid></control><display><type>article</type><title>Pazopanib exposure decreases as a result of an ifosfamide-dependent drug–drug interaction: results of a phase I study</title><source>MEDLINE</source><source>Nature Journals Online</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><source>SpringerLink Journals - AutoHoldings</source><creator>Hamberg, P ; Boers-Sonderen, M J ; van der Graaf, W T A ; de Bruijn, P ; Suttle, A B ; Eskens, F A L M ; Verweij, J ; van Herpen, C M L ; Sleijfer, S</creator><creatorcontrib>Hamberg, P ; Boers-Sonderen, M J ; van der Graaf, W T A ; de Bruijn, P ; Suttle, A B ; Eskens, F A L M ; Verweij, J ; van Herpen, C M L ; Sleijfer, S</creatorcontrib><description>Background:
The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1–3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.
Methods:
In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m
−2
per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.
Results:
Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.
Conclusion:
Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m
−2
per cycle, every 3 weeks) is 800 mg daily.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/bjc.2013.798</identifier><identifier>PMID: 24366297</identifier><identifier>CODEN: BJCAAI</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154/436/108 ; 692/699/67/1798 ; 692/700/565/1436/1437 ; Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols - administration & dosage ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cancer therapies ; Chemotherapy ; Clinical Study ; Cytotoxicity ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug dosages ; Drug Interactions ; Drug Resistance ; Endothelial Cells - cytology ; Epidemiology ; Female ; Humans ; Hypertension ; Ifosfamide - adverse effects ; Ifosfamide - pharmacokinetics ; Ifosfamide - therapeutic use ; Kinases ; Male ; Medical research ; Medical sciences ; Metastasis ; Middle Aged ; Molecular Medicine ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Neoplasms - drug therapy ; Neutropenia ; Oncology ; Patients ; Pharmacokinetics ; Placenta Growth Factor ; Pregnancy Proteins - blood ; Pyrimidines - adverse effects ; Pyrimidines - pharmacokinetics ; Pyrimidines - therapeutic use ; Sarcoma ; Sulfonamides - adverse effects ; Sulfonamides - pharmacokinetics ; Sulfonamides - therapeutic use ; Toxicity ; Tumors ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - blood ; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors ; Vascular Endothelial Growth Factor Receptor-2 - blood ; Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors ; Young Adult</subject><ispartof>British journal of cancer, 2014-02, Vol.110 (4), p.888-893</ispartof><rights>The Author(s) 2014</rights><rights>2015 INIST-CNRS</rights><rights>Copyright Nature Publishing Group Feb 18, 2014</rights><rights>Copyright © 2014 Cancer Research UK 2014 Cancer Research UK</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c480t-e8dd8bea01a90bd1737bae7aee4175819d8f16d569b2b3e44f3da134d6c6775e3</citedby><cites>FETCH-LOGICAL-c480t-e8dd8bea01a90bd1737bae7aee4175819d8f16d569b2b3e44f3da134d6c6775e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929878/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929878/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28216850$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24366297$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamberg, P</creatorcontrib><creatorcontrib>Boers-Sonderen, M J</creatorcontrib><creatorcontrib>van der Graaf, W T A</creatorcontrib><creatorcontrib>de Bruijn, P</creatorcontrib><creatorcontrib>Suttle, A B</creatorcontrib><creatorcontrib>Eskens, F A L M</creatorcontrib><creatorcontrib>Verweij, J</creatorcontrib><creatorcontrib>van Herpen, C M L</creatorcontrib><creatorcontrib>Sleijfer, S</creatorcontrib><title>Pazopanib exposure decreases as a result of an ifosfamide-dependent drug–drug interaction: results of a phase I study</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background:
The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1–3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.
Methods:
In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m
−2
per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.
Results:
Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.
Conclusion:
Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m
−2
per cycle, every 3 weeks) is 800 mg daily.</description><subject>631/154/436/108</subject><subject>692/699/67/1798</subject><subject>692/700/565/1436/1437</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cancer therapies</subject><subject>Chemotherapy</subject><subject>Clinical Study</subject><subject>Cytotoxicity</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Schedule</subject><subject>Drug dosages</subject><subject>Drug Interactions</subject><subject>Drug Resistance</subject><subject>Endothelial Cells - cytology</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Humans</subject><subject>Hypertension</subject><subject>Ifosfamide - adverse effects</subject><subject>Ifosfamide - pharmacokinetics</subject><subject>Ifosfamide - therapeutic use</subject><subject>Kinases</subject><subject>Male</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Metastasis</subject><subject>Middle Aged</subject><subject>Molecular Medicine</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Neoplasms - drug therapy</subject><subject>Neutropenia</subject><subject>Oncology</subject><subject>Patients</subject><subject>Pharmacokinetics</subject><subject>Placenta Growth Factor</subject><subject>Pregnancy Proteins - blood</subject><subject>Pyrimidines - adverse effects</subject><subject>Pyrimidines - pharmacokinetics</subject><subject>Pyrimidines - therapeutic use</subject><subject>Sarcoma</subject><subject>Sulfonamides - adverse effects</subject><subject>Sulfonamides - pharmacokinetics</subject><subject>Sulfonamides - therapeutic use</subject><subject>Toxicity</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - blood</subject><subject>Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - blood</subject><subject>Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors</subject><subject>Young Adult</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkU1rFEEQhhtRzBq9eZYG8eZs-mOmPzwIEjQGAvGg56ZmumYzy2732D2jxpP_wX_oL0mvu8YIQkFR1FNvvfAS8pSzJWfSnLTrbikYl0ttzT2y4I0UFTdC3ycLxpiumBXsiDzKeV1Gy4x-SI5ELZUSVi_I1w_wPY4QhpbitzHmOSH12CWEjJlCKZowz5uJxp5CoEMfcw_bwWPlccTgMUzUp3n168fPXaNDmDBBNw0xvDqc5t-3dLwqmvSc5mn214_Jgx42GZ8c-jH59O7tx9P31cXl2fnpm4uqqw2bKjTemxaBcbCs9VxL3QJqQKy5bgy33vRc-UbZVrQS67qXHrisveqU1g3KY_J6rzvO7RZ9V-wm2LgxDVtI1y7C4P7dhOHKreIXJ62wRpsi8PwgkOLnGfPk1nFOoXh2vLZWSaFqWaiXe6pLMeeE_e0HztwuJldicruYXImp4M_uurqF_-RSgBcHAHIHmz5B6Ib8lzOCK9OwwlV7LpdVWGG64-5_j28AnHKtwg</recordid><startdate>20140218</startdate><enddate>20140218</enddate><creator>Hamberg, P</creator><creator>Boers-Sonderen, M J</creator><creator>van der Graaf, W T A</creator><creator>de Bruijn, P</creator><creator>Suttle, A B</creator><creator>Eskens, F A L M</creator><creator>Verweij, J</creator><creator>van Herpen, C M L</creator><creator>Sleijfer, S</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope></search><sort><creationdate>20140218</creationdate><title>Pazopanib exposure decreases as a result of an ifosfamide-dependent drug–drug interaction: results of a phase I study</title><author>Hamberg, P ; Boers-Sonderen, M J ; van der Graaf, W T A ; de Bruijn, P ; Suttle, A B ; Eskens, F A L M ; Verweij, J ; van Herpen, C M L ; Sleijfer, S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c480t-e8dd8bea01a90bd1737bae7aee4175819d8f16d569b2b3e44f3da134d6c6775e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>631/154/436/108</topic><topic>692/699/67/1798</topic><topic>692/700/565/1436/1437</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic Combined Chemotherapy Protocols - administration & dosage</topic><topic>Antineoplastic Combined Chemotherapy Protocols - adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Cancer therapies</topic><topic>Chemotherapy</topic><topic>Clinical Study</topic><topic>Cytotoxicity</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Administration Schedule</topic><topic>Drug dosages</topic><topic>Drug Interactions</topic><topic>Drug Resistance</topic><topic>Endothelial Cells - cytology</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Humans</topic><topic>Hypertension</topic><topic>Ifosfamide - adverse effects</topic><topic>Ifosfamide - pharmacokinetics</topic><topic>Ifosfamide - therapeutic use</topic><topic>Kinases</topic><topic>Male</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>Metastasis</topic><topic>Middle Aged</topic><topic>Molecular Medicine</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Neoplasms - drug therapy</topic><topic>Neutropenia</topic><topic>Oncology</topic><topic>Patients</topic><topic>Pharmacokinetics</topic><topic>Placenta Growth Factor</topic><topic>Pregnancy Proteins - blood</topic><topic>Pyrimidines - adverse effects</topic><topic>Pyrimidines - pharmacokinetics</topic><topic>Pyrimidines - therapeutic use</topic><topic>Sarcoma</topic><topic>Sulfonamides - adverse effects</topic><topic>Sulfonamides - pharmacokinetics</topic><topic>Sulfonamides - therapeutic use</topic><topic>Toxicity</topic><topic>Tumors</topic><topic>Vascular endothelial growth factor</topic><topic>Vascular Endothelial Growth Factor A - blood</topic><topic>Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors</topic><topic>Vascular Endothelial Growth Factor Receptor-2 - blood</topic><topic>Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hamberg, P</creatorcontrib><creatorcontrib>Boers-Sonderen, M J</creatorcontrib><creatorcontrib>van der Graaf, W T A</creatorcontrib><creatorcontrib>de Bruijn, P</creatorcontrib><creatorcontrib>Suttle, A B</creatorcontrib><creatorcontrib>Eskens, F A L M</creatorcontrib><creatorcontrib>Verweij, J</creatorcontrib><creatorcontrib>van Herpen, C M L</creatorcontrib><creatorcontrib>Sleijfer, S</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</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 Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hamberg, P</au><au>Boers-Sonderen, M J</au><au>van der Graaf, W T A</au><au>de Bruijn, P</au><au>Suttle, A B</au><au>Eskens, F A L M</au><au>Verweij, J</au><au>van Herpen, C M L</au><au>Sleijfer, S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pazopanib exposure decreases as a result of an ifosfamide-dependent drug–drug interaction: results of a phase I study</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2014-02-18</date><risdate>2014</risdate><volume>110</volume><issue>4</issue><spage>888</spage><epage>893</epage><pages>888-893</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><coden>BJCAAI</coden><abstract>Background:
The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1–3, has activity as single agent and is attractive to enhance anti-tumour activity of chemotherapy. We conducted a dose-finding and pharmacokinetic (PK)/pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide.
Methods:
In a 3+3+3 design, patients with advanced solid tumours received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9 g m
−2
per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers.
Results:
Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000 mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide.
Conclusion:
Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9 g m
−2
per cycle, every 3 weeks) is 800 mg daily.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24366297</pmid><doi>10.1038/bjc.2013.798</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | British journal of cancer, 2014-02, Vol.110 (4), p.888-893 |
| issn | 0007-0920 1532-1827 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3929878 |
| source | MEDLINE; Nature Journals Online; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SpringerLink Journals - AutoHoldings |
| subjects | 631/154/436/108 692/699/67/1798 692/700/565/1436/1437 Adolescent Adult Aged Antineoplastic Combined Chemotherapy Protocols - administration & dosage Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Biomedical and Life Sciences Biomedicine Cancer Research Cancer therapies Chemotherapy Clinical Study Cytotoxicity Dose-Response Relationship, Drug Drug Administration Schedule Drug dosages Drug Interactions Drug Resistance Endothelial Cells - cytology Epidemiology Female Humans Hypertension Ifosfamide - adverse effects Ifosfamide - pharmacokinetics Ifosfamide - therapeutic use Kinases Male Medical research Medical sciences Metastasis Middle Aged Molecular Medicine Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Neoplasms - drug therapy Neutropenia Oncology Patients Pharmacokinetics Placenta Growth Factor Pregnancy Proteins - blood Pyrimidines - adverse effects Pyrimidines - pharmacokinetics Pyrimidines - therapeutic use Sarcoma Sulfonamides - adverse effects Sulfonamides - pharmacokinetics Sulfonamides - therapeutic use Toxicity Tumors Vascular endothelial growth factor Vascular Endothelial Growth Factor A - blood Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - blood Vascular Endothelial Growth Factor Receptor-3 - antagonists & inhibitors Young Adult |
| title | Pazopanib exposure decreases as a result of an ifosfamide-dependent drug–drug interaction: results of a phase I study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T13%3A21%3A41IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pazopanib%20exposure%20decreases%20as%20a%20result%20of%20an%20ifosfamide-dependent%20drug%E2%80%93drug%20interaction:%20results%20of%20a%20phase%20I%20study&rft.jtitle=British%20journal%20of%20cancer&rft.au=Hamberg,%20P&rft.date=2014-02-18&rft.volume=110&rft.issue=4&rft.spage=888&rft.epage=893&rft.pages=888-893&rft.issn=0007-0920&rft.eissn=1532-1827&rft.coden=BJCAAI&rft_id=info:doi/10.1038/bjc.2013.798&rft_dat=%3Cproquest_pubme%3E3222400501%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1499632643&rft_id=info:pmid/24366297&rfr_iscdi=true |