Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice
Aim： The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor （EGFR-TKI）. Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenogra...
Gespeichert in:
| Veröffentlicht in: | Acta pharmacologica Sinica 2016-06, Vol.37 (6), p.825-833 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 833 |
|---|---|
| container_issue | 6 |
| container_start_page | 825 |
| container_title | Acta pharmacologica Sinica |
| container_volume | 37 |
| creator | Ji, Xi-wei Ji, Shuang-min Li, Run-tao Wu, Ke-hua Zhu, Xiao Lu, Wei Zhou, Tian-yan |
| description | Aim： The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor （EGFR-TKI）. Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods： Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 （50 or 150 mg.kg-l.d-1, ig） or vehicle for 18 d. The pharmacokinetics （PK） and pharmacodynamics （PD） of TM208 were evaluated. Results： The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC5o （55.9 pg/L）, as well as three parameters （＇a＇ of 27.2%, ＇b＇ of 2730%, ＇c＇ of 0.58 h1） denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/ transit compartment model with estimated parameters associated with tumor growth characteristics kog （0.282 day-1）, drug potency kTM208 （0.0499 cm3/day） and the kinetics of tumor cell death k1 （0.141 day-1）, which provided insight into drug mechanisms and behaviors. Conclusion： The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance. |
| doi_str_mv | 10.1038/aps.2016.40 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4954772</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><cqvip_id>669083206</cqvip_id><sourcerecordid>1793566414</sourcerecordid><originalsourceid>FETCH-LOGICAL-c506t-61bdb5c9b7058f3c9b359c9d1594b9e43584406a05ca2468e1449cd47e4a28573</originalsourceid><addsrcrecordid>eNqFkk1v1DAQhiMEoqVw4o4suCBBFn87viChqi0VRSC0nC3HcRKXjb21HUR_AX8bR7usCkLi5PHM43fG9ltVTxFcIUiaN3qbVhgivqLwXnWMBGW1wIzeLzEXqKawIUfVo5SuISSYIPmwOsICEUIgOa5-fh51nLQJ35y32Zl6u993t15PzoApdHbj_ABCD_JogfbZ5XkKEdi-tyYv-fVHDJtS6cDZxfmXev3hEkSbXMraGwucB-M8aQ_aaHXKwCzZCH5YH4ao-wxKG_u4etDrTbJP9utJ9fX8bH36vr76dHF5-u6qNgzyXHPUdi0zshWQNT0pAWHSyA4xSVtpKWENpZBryIzGlDcWUSpNR4WlGjdMkJPq7U53O7eT7Yz1OeqN2kY36Xirgnbqz4p3oxrCd0Ulo0LgIvByLxDDzWxTVpNLxm422tswJ4Ua2HCBMZL_R4UkjHOKaEFf_IVehzn68hILhYUgqOGFerWjTAwpRdsf5kZQLV5QxQtq8YKisNDP7l71wP7-_AK83gGplPxg452m_9R7vu8-Bj_clBMHSc5lcRmGnPwCYc3Jzw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1792773186</pqid></control><display><type>article</type><title>Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice</title><source>Open Access: PubMed Central</source><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Ji, Xi-wei ; Ji, Shuang-min ; Li, Run-tao ; Wu, Ke-hua ; Zhu, Xiao ; Lu, Wei ; Zhou, Tian-yan</creator><creatorcontrib>Ji, Xi-wei ; Ji, Shuang-min ; Li, Run-tao ; Wu, Ke-hua ; Zhu, Xiao ; Lu, Wei ; Zhou, Tian-yan</creatorcontrib><description>Aim： The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor （EGFR-TKI）. Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods： Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 （50 or 150 mg.kg-l.d-1, ig） or vehicle for 18 d. The pharmacokinetics （PK） and pharmacodynamics （PD） of TM208 were evaluated. Results： The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC5o （55.9 pg/L）, as well as three parameters （＇a＇ of 27.2%, ＇b＇ of 2730%, ＇c＇ of 0.58 h1） denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/ transit compartment model with estimated parameters associated with tumor growth characteristics kog （0.282 day-1）, drug potency kTM208 （0.0499 cm3/day） and the kinetics of tumor cell death k1 （0.141 day-1）, which provided insight into drug mechanisms and behaviors. Conclusion： The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.</description><identifier>ISSN: 1671-4083</identifier><identifier>EISSN: 1745-7254</identifier><identifier>DOI: 10.1038/aps.2016.40</identifier><identifier>PMID: 27133303</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Animals ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Agents - therapeutic use ; Biomedical and Life Sciences ; Biomedicine ; Breast - drug effects ; Breast - metabolism ; Breast - pathology ; Breast Neoplasms - drug therapy ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; CYP3A ; Drug Resistance, Neoplasm ; Female ; Humans ; Immunology ; Internal Medicine ; Medical Microbiology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Models, Biological ; Original ; original-article ; Pharmacology/Toxicology ; Piperazines - pharmacokinetics ; Piperazines - pharmacology ; Piperazines - therapeutic use ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - metabolism ; Vaccine ; 乳腺癌 ; 小鼠 ; 抗肿瘤作用 ; 模型描述 ; 电阻 ; 药效学 ; 药物动力学</subject><ispartof>Acta pharmacologica Sinica, 2016-06, Vol.37 (6), p.825-833</ispartof><rights>CPS and SIMM 2016</rights><rights>Copyright Nature Publishing Group Jun 2016</rights><rights>Copyright © 2016 CPS and SIMM 2016 CPS and SIMM</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c506t-61bdb5c9b7058f3c9b359c9d1594b9e43584406a05ca2468e1449cd47e4a28573</citedby><cites>FETCH-LOGICAL-c506t-61bdb5c9b7058f3c9b359c9d1594b9e43584406a05ca2468e1449cd47e4a28573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://image.cqvip.com/vip1000/qk/95561A/95561A.jpg</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954772/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4954772/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27133303$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ji, Xi-wei</creatorcontrib><creatorcontrib>Ji, Shuang-min</creatorcontrib><creatorcontrib>Li, Run-tao</creatorcontrib><creatorcontrib>Wu, Ke-hua</creatorcontrib><creatorcontrib>Zhu, Xiao</creatorcontrib><creatorcontrib>Lu, Wei</creatorcontrib><creatorcontrib>Zhou, Tian-yan</creatorcontrib><title>Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice</title><title>Acta pharmacologica Sinica</title><addtitle>Acta Pharmacol Sin</addtitle><addtitle>Acta Pharmacologica Sinica</addtitle><description>Aim： The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor （EGFR-TKI）. Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods： Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 （50 or 150 mg.kg-l.d-1, ig） or vehicle for 18 d. The pharmacokinetics （PK） and pharmacodynamics （PD） of TM208 were evaluated. Results： The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC5o （55.9 pg/L）, as well as three parameters （＇a＇ of 27.2%, ＇b＇ of 2730%, ＇c＇ of 0.58 h1） denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/ transit compartment model with estimated parameters associated with tumor growth characteristics kog （0.282 day-1）, drug potency kTM208 （0.0499 cm3/day） and the kinetics of tumor cell death k1 （0.141 day-1）, which provided insight into drug mechanisms and behaviors. Conclusion： The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Agents - therapeutic use</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Breast - drug effects</subject><subject>Breast - metabolism</subject><subject>Breast - pathology</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>CYP3A</subject><subject>Drug Resistance, Neoplasm</subject><subject>Female</subject><subject>Humans</subject><subject>Immunology</subject><subject>Internal Medicine</subject><subject>Medical Microbiology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Models, Biological</subject><subject>Original</subject><subject>original-article</subject><subject>Pharmacology/Toxicology</subject><subject>Piperazines - pharmacokinetics</subject><subject>Piperazines - pharmacology</subject><subject>Piperazines - therapeutic use</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Vaccine</subject><subject>乳腺癌</subject><subject>小鼠</subject><subject>抗肿瘤作用</subject><subject>模型描述</subject><subject>电阻</subject><subject>药效学</subject><subject>药物动力学</subject><issn>1671-4083</issn><issn>1745-7254</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkk1v1DAQhiMEoqVw4o4suCBBFn87viChqi0VRSC0nC3HcRKXjb21HUR_AX8bR7usCkLi5PHM43fG9ltVTxFcIUiaN3qbVhgivqLwXnWMBGW1wIzeLzEXqKawIUfVo5SuISSYIPmwOsICEUIgOa5-fh51nLQJ35y32Zl6u993t15PzoApdHbj_ABCD_JogfbZ5XkKEdi-tyYv-fVHDJtS6cDZxfmXev3hEkSbXMraGwucB-M8aQ_aaHXKwCzZCH5YH4ao-wxKG_u4etDrTbJP9utJ9fX8bH36vr76dHF5-u6qNgzyXHPUdi0zshWQNT0pAWHSyA4xSVtpKWENpZBryIzGlDcWUSpNR4WlGjdMkJPq7U53O7eT7Yz1OeqN2kY36Xirgnbqz4p3oxrCd0Ulo0LgIvByLxDDzWxTVpNLxm422tswJ4Ua2HCBMZL_R4UkjHOKaEFf_IVehzn68hILhYUgqOGFerWjTAwpRdsf5kZQLV5QxQtq8YKisNDP7l71wP7-_AK83gGplPxg452m_9R7vu8-Bj_clBMHSc5lcRmGnPwCYc3Jzw</recordid><startdate>20160601</startdate><enddate>20160601</enddate><creator>Ji, Xi-wei</creator><creator>Ji, Shuang-min</creator><creator>Li, Run-tao</creator><creator>Wu, Ke-hua</creator><creator>Zhu, Xiao</creator><creator>Lu, Wei</creator><creator>Zhou, Tian-yan</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>2RA</scope><scope>92L</scope><scope>CQIGP</scope><scope>W91</scope><scope>~WA</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160601</creationdate><title>Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice</title><author>Ji, Xi-wei ; Ji, Shuang-min ; Li, Run-tao ; Wu, Ke-hua ; Zhu, Xiao ; Lu, Wei ; Zhou, Tian-yan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c506t-61bdb5c9b7058f3c9b359c9d1594b9e43584406a05ca2468e1449cd47e4a28573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Agents - therapeutic use</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Breast - drug effects</topic><topic>Breast - metabolism</topic><topic>Breast - pathology</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>CYP3A</topic><topic>Drug Resistance, Neoplasm</topic><topic>Female</topic><topic>Humans</topic><topic>Immunology</topic><topic>Internal Medicine</topic><topic>Medical Microbiology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Models, Biological</topic><topic>Original</topic><topic>original-article</topic><topic>Pharmacology/Toxicology</topic><topic>Piperazines - pharmacokinetics</topic><topic>Piperazines - pharmacology</topic><topic>Piperazines - therapeutic use</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><topic>Receptor, Epidermal Growth Factor - metabolism</topic><topic>Vaccine</topic><topic>乳腺癌</topic><topic>小鼠</topic><topic>抗肿瘤作用</topic><topic>模型描述</topic><topic>电阻</topic><topic>药效学</topic><topic>药物动力学</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ji, Xi-wei</creatorcontrib><creatorcontrib>Ji, Shuang-min</creatorcontrib><creatorcontrib>Li, Run-tao</creatorcontrib><creatorcontrib>Wu, Ke-hua</creatorcontrib><creatorcontrib>Zhu, Xiao</creatorcontrib><creatorcontrib>Lu, Wei</creatorcontrib><creatorcontrib>Zhou, Tian-yan</creatorcontrib><collection>维普_期刊</collection><collection>中文科技期刊数据库-CALIS站点</collection><collection>维普中文期刊数据库</collection><collection>中文科技期刊数据库-医药卫生</collection><collection>中文科技期刊数据库- 镜像站点</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>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Technology Research 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)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</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>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta pharmacologica Sinica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ji, Xi-wei</au><au>Ji, Shuang-min</au><au>Li, Run-tao</au><au>Wu, Ke-hua</au><au>Zhu, Xiao</au><au>Lu, Wei</au><au>Zhou, Tian-yan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice</atitle><jtitle>Acta pharmacologica Sinica</jtitle><stitle>Acta Pharmacol Sin</stitle><addtitle>Acta Pharmacologica Sinica</addtitle><date>2016-06-01</date><risdate>2016</risdate><volume>37</volume><issue>6</issue><spage>825</spage><epage>833</epage><pages>825-833</pages><issn>1671-4083</issn><eissn>1745-7254</eissn><abstract>Aim： The novel anticancer compound TM208 is an EGFR tyrosine kinase inhibitor （EGFR-TKI）. Since the development of resistance to EGFR-TKIs is a major challenge in their clinical usage, we investigated the profiles of resistance following continuous treatment with TM208 in human breast cancer xenograft mice, and identified the relationship between the tumor pEGFR levels and tumor growth inhibition. Methods： Female BALB/c nude mice were implanted with human breast cancer MCF-7 cells, and the xenograft mice received TM208 （50 or 150 mg.kg-l.d-1, ig） or vehicle for 18 d. The pharmacokinetics （PK） and pharmacodynamics （PD） of TM208 were evaluated. Results： The PK properties of TM208 were described by a one-compartment model with first-order absorption kinetics. Our study showed the inhibitory effects of TM208 on tumor pEGFR levels gradually reached a maximum effect, after which it became weaker over time, which was characterized by a combined tolerance/indirect response PD model with an estimated EC5o （55.9 pg/L）, as well as three parameters （＇a＇ of 27.2%, ＇b＇ of 2730%, ＇c＇ of 0.58 h1） denoting the maximum, extent and rate of resistance, respectively. The relationship between the tumor pEGFR levels and tumor growth inhibition was characterized by a combined logistic tumor growth/ transit compartment model with estimated parameters associated with tumor growth characteristics kog （0.282 day-1）, drug potency kTM208 （0.0499 cm3/day） and the kinetics of tumor cell death k1 （0.141 day-1）, which provided insight into drug mechanisms and behaviors. Conclusion： The proposed PK/PD model provides a better understanding of the pharmacological properties of TM208 in the treatment of breast cancer. Furthermore, simulation based on a tolerance model allows prediction of the occurrence of resistance.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27133303</pmid><doi>10.1038/aps.2016.40</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1671-4083 |
| ispartof | Acta pharmacologica Sinica, 2016-06, Vol.37 (6), p.825-833 |
| issn | 1671-4083 1745-7254 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4954772 |
| source | Open Access: PubMed Central; MEDLINE; Alma/SFX Local Collection |
| subjects | Animals Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Biomedical and Life Sciences Biomedicine Breast - drug effects Breast - metabolism Breast - pathology Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Breast Neoplasms - pathology CYP3A Drug Resistance, Neoplasm Female Humans Immunology Internal Medicine Medical Microbiology Mice Mice, Inbred BALB C Mice, Nude Models, Biological Original original-article Pharmacology/Toxicology Piperazines - pharmacokinetics Piperazines - pharmacology Piperazines - therapeutic use Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - metabolism Vaccine 乳腺癌 小鼠 抗肿瘤作用 模型描述 电阻 药效学 药物动力学 |
| title | Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T18%3A45%3A36IST&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=Pharmacokinetic-pharmacodynamic%20modeling%20of%20the%20antitumor%20effect%20of%20TM208%20and%20EGFR-TKI%20resistance%20in%20human%20breast%20cancer%20xenograft%20mice&rft.jtitle=Acta%20pharmacologica%20Sinica&rft.au=Ji,%20Xi-wei&rft.date=2016-06-01&rft.volume=37&rft.issue=6&rft.spage=825&rft.epage=833&rft.pages=825-833&rft.issn=1671-4083&rft.eissn=1745-7254&rft_id=info:doi/10.1038/aps.2016.40&rft_dat=%3Cproquest_pubme%3E1793566414%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=1792773186&rft_id=info:pmid/27133303&rft_cqvip_id=669083206&rfr_iscdi=true |