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Mechanism-based pharmacokinetic/pharmacodynamic model for troxacitabine-induced neutropenia in cancer patients
Purposes The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer. Methods A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A m...
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| Published in: | Cancer chemotherapy and pharmacology 2011-05, Vol.67 (5), p.985-994 |
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| container_end_page | 994 |
| container_issue | 5 |
| container_start_page | 985 |
| container_title | Cancer chemotherapy and pharmacology |
| container_volume | 67 |
| creator | Ng, Chee M. Patnaik, A. Beeram, M. Lin, C. C. Takimoto, C. H. |
| description | Purposes
The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer.
Methods
A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory
E
max
model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit.
Results and conclusions
The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule. |
| doi_str_mv | 10.1007/s00280-010-1393-y |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_863768215</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>863768215</sourcerecordid><originalsourceid>FETCH-LOGICAL-c400t-94d9f0391595df72523205a113f133bf107f520a69dc7458445abd0e459bb9b93</originalsourceid><addsrcrecordid>eNp1kU1LHEEQhhtJiKvmB-QiQyDk1LH6a2f6KJLEgCEXPQ81_aFtZnrG7hnI_nt73TWC4Kko6nnr6yXkE4NvDKA-ywC8AQoMKBNa0M0BWTEpOIVGindkBUJKqmqQh-Qo53sAkEyID-SQw5pJxtmKxN_O3GEMeaAdZmer6Q7TgGb8G6Kbgzl7zu0m4hBMNYzW9ZUfUzWn8R-aMGNXUBqiXUzRR7eUwuRiwCrEymA0LlUTzsHFOZ-Q9x777D7u4zG5-fH9-uKSXv35-evi_IoaCTBTLa32IDRTWllfc8UFB4WMCV8O6DyD2isOuNbW1FI1UirsLDipdNfpTotj8nXXd0rjw-Ly3A4hG9f3GN245LZZi3rdcKYK-fkVeT8uKZbltpCoG_kEsR1k0phzcr6dUhgwbVoG7daKdmdFC9u8WNFuiuZ033jpBmf_K55_X4AvewCzwd6n8qqQXzjJJAe95fiOy6UUb1162fDt6Y9FoKH6</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>863378415</pqid></control><display><type>article</type><title>Mechanism-based pharmacokinetic/pharmacodynamic model for troxacitabine-induced neutropenia in cancer patients</title><source>Springer Nature</source><creator>Ng, Chee M. ; Patnaik, A. ; Beeram, M. ; Lin, C. C. ; Takimoto, C. H.</creator><creatorcontrib>Ng, Chee M. ; Patnaik, A. ; Beeram, M. ; Lin, C. C. ; Takimoto, C. H.</creatorcontrib><description>Purposes
The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer.
Methods
A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory
E
max
model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit.
Results and conclusions
The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-010-1393-y</identifier><identifier>PMID: 20614121</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject><![CDATA[Adult ; Aged ; Antineoplastic agents ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - pharmacokinetics ; Antineoplastic Agents - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Biological and medical sciences ; Cancer Research ; Cisplatin - administration & dosage ; Cytosine - administration & dosage ; Cytosine - analogs & derivatives ; Cytosine - pharmacokinetics ; Cytosine - pharmacology ; Dioxolanes - administration & dosage ; Dioxolanes - pharmacokinetics ; Dioxolanes - pharmacology ; Female ; Hematologic and hematopoietic diseases ; Humans ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Middle Aged ; Models, Biological ; Monte Carlo Method ; Neoplasms - drug therapy ; Neutropenia - chemically induced ; Oncology ; Original Article ; Other diseases. Hematologic involvement in other diseases ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Young Adult]]></subject><ispartof>Cancer chemotherapy and pharmacology, 2011-05, Vol.67 (5), p.985-994</ispartof><rights>Springer-Verlag 2010</rights><rights>2015 INIST-CNRS</rights><rights>Springer-Verlag 2011</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c400t-94d9f0391595df72523205a113f133bf107f520a69dc7458445abd0e459bb9b93</citedby><cites>FETCH-LOGICAL-c400t-94d9f0391595df72523205a113f133bf107f520a69dc7458445abd0e459bb9b93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24142091$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20614121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ng, Chee M.</creatorcontrib><creatorcontrib>Patnaik, A.</creatorcontrib><creatorcontrib>Beeram, M.</creatorcontrib><creatorcontrib>Lin, C. C.</creatorcontrib><creatorcontrib>Takimoto, C. H.</creatorcontrib><title>Mechanism-based pharmacokinetic/pharmacodynamic model for troxacitabine-induced neutropenia in cancer patients</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purposes
The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer.
Methods
A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory
E
max
model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit.
Results and conclusions
The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule.</description><subject>Adult</subject><subject>Aged</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - administration & dosage</subject><subject>Antineoplastic Agents - pharmacokinetics</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Cancer Research</subject><subject>Cisplatin - administration & dosage</subject><subject>Cytosine - administration & dosage</subject><subject>Cytosine - analogs & derivatives</subject><subject>Cytosine - pharmacokinetics</subject><subject>Cytosine - pharmacology</subject><subject>Dioxolanes - administration & dosage</subject><subject>Dioxolanes - pharmacokinetics</subject><subject>Dioxolanes - pharmacology</subject><subject>Female</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Monte Carlo Method</subject><subject>Neoplasms - drug therapy</subject><subject>Neutropenia - chemically induced</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Other diseases. Hematologic involvement in other diseases</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Young Adult</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNp1kU1LHEEQhhtJiKvmB-QiQyDk1LH6a2f6KJLEgCEXPQ81_aFtZnrG7hnI_nt73TWC4Kko6nnr6yXkE4NvDKA-ywC8AQoMKBNa0M0BWTEpOIVGindkBUJKqmqQh-Qo53sAkEyID-SQw5pJxtmKxN_O3GEMeaAdZmer6Q7TgGb8G6Kbgzl7zu0m4hBMNYzW9ZUfUzWn8R-aMGNXUBqiXUzRR7eUwuRiwCrEymA0LlUTzsHFOZ-Q9x777D7u4zG5-fH9-uKSXv35-evi_IoaCTBTLa32IDRTWllfc8UFB4WMCV8O6DyD2isOuNbW1FI1UirsLDipdNfpTotj8nXXd0rjw-Ly3A4hG9f3GN245LZZi3rdcKYK-fkVeT8uKZbltpCoG_kEsR1k0phzcr6dUhgwbVoG7daKdmdFC9u8WNFuiuZ033jpBmf_K55_X4AvewCzwd6n8qqQXzjJJAe95fiOy6UUb1162fDt6Y9FoKH6</recordid><startdate>20110501</startdate><enddate>20110501</enddate><creator>Ng, Chee M.</creator><creator>Patnaik, A.</creator><creator>Beeram, M.</creator><creator>Lin, C. C.</creator><creator>Takimoto, C. H.</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</general><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>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>7X8</scope></search><sort><creationdate>20110501</creationdate><title>Mechanism-based pharmacokinetic/pharmacodynamic model for troxacitabine-induced neutropenia in cancer patients</title><author>Ng, Chee M. ; Patnaik, A. ; Beeram, M. ; Lin, C. C. ; Takimoto, C. H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c400t-94d9f0391595df72523205a113f133bf107f520a69dc7458445abd0e459bb9b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - administration & dosage</topic><topic>Antineoplastic Agents - pharmacokinetics</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Cancer Research</topic><topic>Cisplatin - administration & dosage</topic><topic>Cytosine - administration & dosage</topic><topic>Cytosine - analogs & derivatives</topic><topic>Cytosine - pharmacokinetics</topic><topic>Cytosine - pharmacology</topic><topic>Dioxolanes - administration & dosage</topic><topic>Dioxolanes - pharmacokinetics</topic><topic>Dioxolanes - pharmacology</topic><topic>Female</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Monte Carlo Method</topic><topic>Neoplasms - drug therapy</topic><topic>Neutropenia - chemically induced</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Other diseases. Hematologic involvement in other diseases</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ng, Chee M.</creatorcontrib><creatorcontrib>Patnaik, A.</creatorcontrib><creatorcontrib>Beeram, M.</creatorcontrib><creatorcontrib>Lin, C. C.</creatorcontrib><creatorcontrib>Takimoto, C. H.</creatorcontrib><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>Oncogenes and Growth Factors Abstracts</collection><collection>Health & 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>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 & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ng, Chee M.</au><au>Patnaik, A.</au><au>Beeram, M.</au><au>Lin, C. C.</au><au>Takimoto, C. H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism-based pharmacokinetic/pharmacodynamic model for troxacitabine-induced neutropenia in cancer patients</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2011-05-01</date><risdate>2011</risdate><volume>67</volume><issue>5</issue><spage>985</spage><epage>994</epage><pages>985-994</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>Purposes
The objective of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PK/PD) model in describing troxacitabine-induced neutropenia in patients with cancer.
Methods
A total of 727 PK/PD samples from 31 patients with cancer were included in the analysis. A mechanism-based population PD model was developed to describe neutropenia and the final model consisted of (1) a drug-sensitive uncommitted progenitor cell compartment (2) three transit compartments, and (3) a circulating neutrophil compartment with feedback mechanism. The troxacitabine affected the proliferation of sensitive progenitor cells through an inhibitory
E
max
model. The model parameters were estimated using the MCPEM algorithm that was implemented in a parallel computing platform consisting of a single computer equipped with a quad-core INTEL central processor unit.
Results and conclusions
The mechanism-based PK/PD model developed using parallelized MCPEM method adequately describes the complex relationship between the exposure and absolute neutrophil counts in troxacitabine-treated patients with cancer. The simulation results suggested that the less frequent dosing schedule of troxacitabine used currently in clinical studies was associated with less incidence of neutropenia compared to more frequent dosing schedule.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>20614121</pmid><doi>10.1007/s00280-010-1393-y</doi><tpages>10</tpages></addata></record> |
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| source | Springer Nature |
| subjects | Adult Aged Antineoplastic agents Antineoplastic Agents - administration & dosage Antineoplastic Agents - pharmacokinetics Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Biological and medical sciences Cancer Research Cisplatin - administration & dosage Cytosine - administration & dosage Cytosine - analogs & derivatives Cytosine - pharmacokinetics Cytosine - pharmacology Dioxolanes - administration & dosage Dioxolanes - pharmacokinetics Dioxolanes - pharmacology Female Hematologic and hematopoietic diseases Humans Male Medical sciences Medicine Medicine & Public Health Middle Aged Models, Biological Monte Carlo Method Neoplasms - drug therapy Neutropenia - chemically induced Oncology Original Article Other diseases. Hematologic involvement in other diseases Pharmacology. Drug treatments Pharmacology/Toxicology Young Adult |
| title | Mechanism-based pharmacokinetic/pharmacodynamic model for troxacitabine-induced neutropenia in cancer patients |
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