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Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years
Purpose The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of d...
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| Published in: | Cancer chemotherapy and pharmacology 2013-03, Vol.71 (3), p.749-763 |
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| creator | Kontny, Nina E. Würthwein, Gudrun Joachim, Boos Boddy, Alan V. Krischke, Miriam Fuhr, Uwe Thompson, Patrick A. Jörger, Markus Schellens, Jan H. M. Hempel, Georg |
| description | Purpose
The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.
Methods
Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively. In total, the combined dataset contained 934 doxorubicin and 935 doxorubicinol plasma concentrations from 82 patients [64 adults and 18 children ( |
| doi_str_mv | 10.1007/s00280-013-2069-1 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1312660255</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1312660255</sourcerecordid><originalsourceid>FETCH-LOGICAL-c402t-5ff9328671ed68a6d3c0e86f85bb90e6a580ef666244418b79a532fc569bf9a93</originalsourceid><addsrcrecordid>eNp1kctu1DAUhi0EosPAA7BBlhASm5TjaxJ2VVUuUi8sYB2dODbj4tiDnQj6Nn2WPhkZzVAQEquzON9_LvoIec7gmAHUbwoAb6ACJioOuq3YA7JiUvAKGikekhUIKStVgzwiT0q5BgDJhHhMjrgQTNZCrsiPT2k7B5x8inS7wTyiSd98tJM3hSZHh_Qz5bn3xse31JYJ--DLZrRx2nWRXl5dXpxd0DENNlCXMsVhDlOhGAdqNj4M2UaawmAznTYYqbi7vbGYy1PyyGEo9tmhrsmXd2efTz9U51fvP56enFdGAp8q5VwreKNrZgfdoB6EAdto16i-b8FqVA1Yp7XmUkrW9HWLSnBnlG5712Ir1uT1fu42p-_z8kA3-mJsCBhtmkvHBONaA1dqQV_-g16nOcfluoUCplgNii8U21Mmp1Kydd02-xHzTceg21np9la6xUq3s7KE1-TFYfLcj3a4T_zWsACvDgAWg8FljMaXP1ytGYh29w3fc2Vpxa82_3Xif7f_AqjppJQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1301517052</pqid></control><display><type>article</type><title>Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years</title><source>Springer Nature</source><creator>Kontny, Nina E. ; Würthwein, Gudrun ; Joachim, Boos ; Boddy, Alan V. ; Krischke, Miriam ; Fuhr, Uwe ; Thompson, Patrick A. ; Jörger, Markus ; Schellens, Jan H. M. ; Hempel, Georg</creator><creatorcontrib>Kontny, Nina E. ; Würthwein, Gudrun ; Joachim, Boos ; Boddy, Alan V. ; Krischke, Miriam ; Fuhr, Uwe ; Thompson, Patrick A. ; Jörger, Markus ; Schellens, Jan H. M. ; Hempel, Georg</creatorcontrib><description>Purpose
The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.
Methods
Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively. In total, the combined dataset contained 934 doxorubicin and 935 doxorubicinol plasma concentrations from 82 patients [64 adults and 18 children (<18 years)]. With this combined dataset, a population pharmacokinetic model was developed, using NONMEM
®
7.2 and a predefined model-building strategy. Different structural models, error models and estimation methods were tested, and the inter-individual and the inter-occasion variability (variability between separate (two or three) doxorubicin infusions) were tested. Using a subset of 52 patients, the influence of different covariates on the pharmacokinetic parameters was investigated. The pharmacokinetic parameter estimates obtained from doxorubicin concentrations with the best model were fixed, and an additional compartment for doxorubicinol was added to the model. With the final model for both substances, a potential age dependency and body mass index dependency of the clearance of doxorubicin and doxorubicinol as well as of the volumes of distribution of the central and the metabolite compartment were evaluated.
Results
A four-compartment model best described the doxorubicin and doxorubicinol data of the combined dataset. This model included a proportional residual error model and an inter-individual variability on the clearance of doxorubicin, on the inter-compartmental clearances of the peripheral compartments, on the clearance of doxorubicinol and on the volumes of distribution of the central, one peripheral and the metabolite compartment. Furthermore, the body surface area as covariate on all pharmacokinetic parameters and an inter-occasion variability for the clearance of doxorubicin and the volume of distribution of the central compartment were incorporated in the model. For a patient with the body surface area of 1.8 m², the clearance of doxorubicin was 53.3 L/h (inter-individual variability 31 %, inter-occasion variability 13 %) and the volume of distribution of the central compartment was 17.7 L (inter-individual variability 19 %, inter-occasion variability 21 %), respectively. The residual variability of the model was 22 % for doxorubicin and 26 % for doxorubicinol. The clearance of doxorubicinol was estimated at 44 L/h (inter-individual variability 50 %) and the volume of distribution of the metabolite compartment at 1,150 L (inter-individual variability 57 %). The evaluation of a possible age dependency and body mass index dependency showed a trend to a smaller volume of distribution of the central compartment (normalised to the body surface area) and a higher volume of distribution of the metabolite compartment (normalised to the body weight) in younger patients.
Conclusions
A four-compartment NONMEM
®
model for doxorubicin and doxorubicinol adequately described the plasma concentrations in adults and children (>3 years). No pronounced effects of age on the clearance of doxorubicin or doxorubicinol were found, and the analysis did not support the modification of the dosing strategies presently used in children and adults.</description><identifier>ISSN: 0344-5704</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-013-2069-1</identifier><identifier>PMID: 23314734</identifier><identifier>CODEN: CCPHDZ</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adolescent ; Adult ; Aged ; Aged, 80 and over ; Aging - metabolism ; Analysis of Variance ; Antibiotics, Antineoplastic - administration & dosage ; Antibiotics, Antineoplastic - pharmacokinetics ; Antineoplastic agents ; Biological and medical sciences ; Biotransformation ; Body Mass Index ; Cancer Research ; Child ; Child, Preschool ; Databases, Factual ; Dose-Response Relationship, Drug ; Doxorubicin - administration & dosage ; Doxorubicin - pharmacokinetics ; Humans ; Infusions, Intravenous ; Medical sciences ; Medicine ; Medicine & Public Health ; Middle Aged ; Models, Statistical ; Oncology ; Original Article ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Population ; Reproducibility of Results ; Young Adult</subject><ispartof>Cancer chemotherapy and pharmacology, 2013-03, Vol.71 (3), p.749-763</ispartof><rights>Springer-Verlag Berlin Heidelberg 2013</rights><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-5ff9328671ed68a6d3c0e86f85bb90e6a580ef666244418b79a532fc569bf9a93</citedby><cites>FETCH-LOGICAL-c402t-5ff9328671ed68a6d3c0e86f85bb90e6a580ef666244418b79a532fc569bf9a93</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=27610399$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23314734$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kontny, Nina E.</creatorcontrib><creatorcontrib>Würthwein, Gudrun</creatorcontrib><creatorcontrib>Joachim, Boos</creatorcontrib><creatorcontrib>Boddy, Alan V.</creatorcontrib><creatorcontrib>Krischke, Miriam</creatorcontrib><creatorcontrib>Fuhr, Uwe</creatorcontrib><creatorcontrib>Thompson, Patrick A.</creatorcontrib><creatorcontrib>Jörger, Markus</creatorcontrib><creatorcontrib>Schellens, Jan H. M.</creatorcontrib><creatorcontrib>Hempel, Georg</creatorcontrib><title>Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.
Methods
Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively. In total, the combined dataset contained 934 doxorubicin and 935 doxorubicinol plasma concentrations from 82 patients [64 adults and 18 children (<18 years)]. With this combined dataset, a population pharmacokinetic model was developed, using NONMEM
®
7.2 and a predefined model-building strategy. Different structural models, error models and estimation methods were tested, and the inter-individual and the inter-occasion variability (variability between separate (two or three) doxorubicin infusions) were tested. Using a subset of 52 patients, the influence of different covariates on the pharmacokinetic parameters was investigated. The pharmacokinetic parameter estimates obtained from doxorubicin concentrations with the best model were fixed, and an additional compartment for doxorubicinol was added to the model. With the final model for both substances, a potential age dependency and body mass index dependency of the clearance of doxorubicin and doxorubicinol as well as of the volumes of distribution of the central and the metabolite compartment were evaluated.
Results
A four-compartment model best described the doxorubicin and doxorubicinol data of the combined dataset. This model included a proportional residual error model and an inter-individual variability on the clearance of doxorubicin, on the inter-compartmental clearances of the peripheral compartments, on the clearance of doxorubicinol and on the volumes of distribution of the central, one peripheral and the metabolite compartment. Furthermore, the body surface area as covariate on all pharmacokinetic parameters and an inter-occasion variability for the clearance of doxorubicin and the volume of distribution of the central compartment were incorporated in the model. For a patient with the body surface area of 1.8 m², the clearance of doxorubicin was 53.3 L/h (inter-individual variability 31 %, inter-occasion variability 13 %) and the volume of distribution of the central compartment was 17.7 L (inter-individual variability 19 %, inter-occasion variability 21 %), respectively. The residual variability of the model was 22 % for doxorubicin and 26 % for doxorubicinol. The clearance of doxorubicinol was estimated at 44 L/h (inter-individual variability 50 %) and the volume of distribution of the metabolite compartment at 1,150 L (inter-individual variability 57 %). The evaluation of a possible age dependency and body mass index dependency showed a trend to a smaller volume of distribution of the central compartment (normalised to the body surface area) and a higher volume of distribution of the metabolite compartment (normalised to the body weight) in younger patients.
Conclusions
A four-compartment NONMEM
®
model for doxorubicin and doxorubicinol adequately described the plasma concentrations in adults and children (>3 years). No pronounced effects of age on the clearance of doxorubicin or doxorubicinol were found, and the analysis did not support the modification of the dosing strategies presently used in children and adults.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Aging - metabolism</subject><subject>Analysis of Variance</subject><subject>Antibiotics, Antineoplastic - administration & dosage</subject><subject>Antibiotics, Antineoplastic - pharmacokinetics</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Biotransformation</subject><subject>Body Mass Index</subject><subject>Cancer Research</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Databases, Factual</subject><subject>Dose-Response Relationship, Drug</subject><subject>Doxorubicin - administration & dosage</subject><subject>Doxorubicin - pharmacokinetics</subject><subject>Humans</subject><subject>Infusions, Intravenous</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Middle Aged</subject><subject>Models, Statistical</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Population</subject><subject>Reproducibility of Results</subject><subject>Young Adult</subject><issn>0344-5704</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp1kctu1DAUhi0EosPAA7BBlhASm5TjaxJ2VVUuUi8sYB2dODbj4tiDnQj6Nn2WPhkZzVAQEquzON9_LvoIec7gmAHUbwoAb6ACJioOuq3YA7JiUvAKGikekhUIKStVgzwiT0q5BgDJhHhMjrgQTNZCrsiPT2k7B5x8inS7wTyiSd98tJM3hSZHh_Qz5bn3xse31JYJ--DLZrRx2nWRXl5dXpxd0DENNlCXMsVhDlOhGAdqNj4M2UaawmAznTYYqbi7vbGYy1PyyGEo9tmhrsmXd2efTz9U51fvP56enFdGAp8q5VwreKNrZgfdoB6EAdto16i-b8FqVA1Yp7XmUkrW9HWLSnBnlG5712Ir1uT1fu42p-_z8kA3-mJsCBhtmkvHBONaA1dqQV_-g16nOcfluoUCplgNii8U21Mmp1Kydd02-xHzTceg21np9la6xUq3s7KE1-TFYfLcj3a4T_zWsACvDgAWg8FljMaXP1ytGYh29w3fc2Vpxa82_3Xif7f_AqjppJQ</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Kontny, Nina E.</creator><creator>Würthwein, Gudrun</creator><creator>Joachim, Boos</creator><creator>Boddy, Alan V.</creator><creator>Krischke, Miriam</creator><creator>Fuhr, Uwe</creator><creator>Thompson, Patrick A.</creator><creator>Jörger, Markus</creator><creator>Schellens, Jan H. M.</creator><creator>Hempel, Georg</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>20130301</creationdate><title>Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years</title><author>Kontny, Nina E. ; Würthwein, Gudrun ; Joachim, Boos ; Boddy, Alan V. ; Krischke, Miriam ; Fuhr, Uwe ; Thompson, Patrick A. ; Jörger, Markus ; Schellens, Jan H. M. ; Hempel, Georg</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-5ff9328671ed68a6d3c0e86f85bb90e6a580ef666244418b79a532fc569bf9a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Aging - metabolism</topic><topic>Analysis of Variance</topic><topic>Antibiotics, Antineoplastic - administration & dosage</topic><topic>Antibiotics, Antineoplastic - pharmacokinetics</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Biotransformation</topic><topic>Body Mass Index</topic><topic>Cancer Research</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Databases, Factual</topic><topic>Dose-Response Relationship, Drug</topic><topic>Doxorubicin - administration & dosage</topic><topic>Doxorubicin - pharmacokinetics</topic><topic>Humans</topic><topic>Infusions, Intravenous</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Middle Aged</topic><topic>Models, Statistical</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Population</topic><topic>Reproducibility of Results</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kontny, Nina E.</creatorcontrib><creatorcontrib>Würthwein, Gudrun</creatorcontrib><creatorcontrib>Joachim, Boos</creatorcontrib><creatorcontrib>Boddy, Alan V.</creatorcontrib><creatorcontrib>Krischke, Miriam</creatorcontrib><creatorcontrib>Fuhr, Uwe</creatorcontrib><creatorcontrib>Thompson, Patrick A.</creatorcontrib><creatorcontrib>Jörger, Markus</creatorcontrib><creatorcontrib>Schellens, Jan H. M.</creatorcontrib><creatorcontrib>Hempel, Georg</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 Medical & Health Databases)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database (ProQuest Medical & Health Databases)</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 & 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>Kontny, Nina E.</au><au>Würthwein, Gudrun</au><au>Joachim, Boos</au><au>Boddy, Alan V.</au><au>Krischke, Miriam</au><au>Fuhr, Uwe</au><au>Thompson, Patrick A.</au><au>Jörger, Markus</au><au>Schellens, Jan H. M.</au><au>Hempel, Georg</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>71</volume><issue>3</issue><spage>749</spage><epage>763</epage><pages>749-763</pages><issn>0344-5704</issn><eissn>1432-0843</eissn><coden>CCPHDZ</coden><abstract>Purpose
The aim of the current investigation was to develop a population pharmacokinetic model for doxorubicin and doxorubicinol that could provide improved estimated values for the pharmacokinetic parameters clearance of doxorubicin, volume of distribution of the central compartment, clearance of doxorubicinol and volume of distribution of the metabolite compartment for adults and children older than 3 years. A further aim was to investigate the potential influence of the covariates body surface area, body weight, body height, age, body mass index, sex and lean body mass on the pharmacokinetic parameters.
Methods
Three different datasets, two containing data from adults and one containing data from adults and children, were merged and the combined dataset was analysed retrospectively. In total, the combined dataset contained 934 doxorubicin and 935 doxorubicinol plasma concentrations from 82 patients [64 adults and 18 children (<18 years)]. With this combined dataset, a population pharmacokinetic model was developed, using NONMEM
®
7.2 and a predefined model-building strategy. Different structural models, error models and estimation methods were tested, and the inter-individual and the inter-occasion variability (variability between separate (two or three) doxorubicin infusions) were tested. Using a subset of 52 patients, the influence of different covariates on the pharmacokinetic parameters was investigated. The pharmacokinetic parameter estimates obtained from doxorubicin concentrations with the best model were fixed, and an additional compartment for doxorubicinol was added to the model. With the final model for both substances, a potential age dependency and body mass index dependency of the clearance of doxorubicin and doxorubicinol as well as of the volumes of distribution of the central and the metabolite compartment were evaluated.
Results
A four-compartment model best described the doxorubicin and doxorubicinol data of the combined dataset. This model included a proportional residual error model and an inter-individual variability on the clearance of doxorubicin, on the inter-compartmental clearances of the peripheral compartments, on the clearance of doxorubicinol and on the volumes of distribution of the central, one peripheral and the metabolite compartment. Furthermore, the body surface area as covariate on all pharmacokinetic parameters and an inter-occasion variability for the clearance of doxorubicin and the volume of distribution of the central compartment were incorporated in the model. For a patient with the body surface area of 1.8 m², the clearance of doxorubicin was 53.3 L/h (inter-individual variability 31 %, inter-occasion variability 13 %) and the volume of distribution of the central compartment was 17.7 L (inter-individual variability 19 %, inter-occasion variability 21 %), respectively. The residual variability of the model was 22 % for doxorubicin and 26 % for doxorubicinol. The clearance of doxorubicinol was estimated at 44 L/h (inter-individual variability 50 %) and the volume of distribution of the metabolite compartment at 1,150 L (inter-individual variability 57 %). The evaluation of a possible age dependency and body mass index dependency showed a trend to a smaller volume of distribution of the central compartment (normalised to the body surface area) and a higher volume of distribution of the metabolite compartment (normalised to the body weight) in younger patients.
Conclusions
A four-compartment NONMEM
®
model for doxorubicin and doxorubicinol adequately described the plasma concentrations in adults and children (>3 years). No pronounced effects of age on the clearance of doxorubicin or doxorubicinol were found, and the analysis did not support the modification of the dosing strategies presently used in children and adults.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>23314734</pmid><doi>10.1007/s00280-013-2069-1</doi><tpages>15</tpages></addata></record> |
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| ispartof | Cancer chemotherapy and pharmacology, 2013-03, Vol.71 (3), p.749-763 |
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| source | Springer Nature |
| subjects | Adolescent Adult Aged Aged, 80 and over Aging - metabolism Analysis of Variance Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - pharmacokinetics Antineoplastic agents Biological and medical sciences Biotransformation Body Mass Index Cancer Research Child Child, Preschool Databases, Factual Dose-Response Relationship, Drug Doxorubicin - administration & dosage Doxorubicin - pharmacokinetics Humans Infusions, Intravenous Medical sciences Medicine Medicine & Public Health Middle Aged Models, Statistical Oncology Original Article Pharmacology. Drug treatments Pharmacology/Toxicology Population Reproducibility of Results Young Adult |
| title | Population pharmacokinetics of doxorubicin: establishment of a NONMEM model for adults and children older than 3 years |
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