Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents
Background Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient. Objective The object...
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| Veröffentlicht in: | Clinical pharmacokinetics 2020-05, Vol.59 (5), p.643-654 |
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| creator | Gade, Christina Sverrisdóttir, Eva Dalhoff, Kim Sonne, Jesper Johansen, Mia Østergaard Christensen, Hanne Rolighed Burhenne, Jürgen Mikus, Gerd Holm, Jens Christian Lund, Trine Meldgaard Holst, Helle |
| description | Background
Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.
Objective
The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11–18 years.
Methods
All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration–time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters.
Results
Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations.
Conclusions
The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity.
Trial registration
EudraCT: 2014-004554-34. |
| doi_str_mv | 10.1007/s40262-019-00838-1 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2404394196</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2404394196</sourcerecordid><originalsourceid>FETCH-LOGICAL-c441t-12013f92a04e02613d24e921f21746586c681c39a72a5b54a1301c19be85bf643</originalsourceid><addsrcrecordid>eNp9kMtOwzAQRS0EoqXwAyxQJNYGj-08vKwqniqUBawtx3FoSmIXO13A12OaAjtW1nju3LlzEDoFcgGE5JeBE5pRTEBgQgpWYNhDY4BcYBA020djwoDiVGRshI5CWJGoooQcohGDnKdFxsfo_qGp1KdrVZc8LZXvlHZvjTV9o0PS2GRRmmASZavk0VnsttVs2bSVN3b7Pa1ca4I2tg_H6KBWbTAnu3eCXq6vnme3eL64uZtN51hzDj0GSoDVgirCTcwPrKLcCAo1jaGymEpnBWgmVE5VWqZcASOgQZSmSMs642yCzgfftXfvGxN6uXIbb-NKSTnhTHCIJ08QHVTauxC8qeXaN53yHxKI_MYnB3wy4pNbfBLi0NnOelN2pvod-eEVBWwQhNiyr8b_7f7H9gvzE3hQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2404394196</pqid></control><display><type>article</type><title>Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents</title><source>SpringerNature Journals</source><creator>Gade, Christina ; Sverrisdóttir, Eva ; Dalhoff, Kim ; Sonne, Jesper ; Johansen, Mia Østergaard ; Christensen, Hanne Rolighed ; Burhenne, Jürgen ; Mikus, Gerd ; Holm, Jens Christian ; Lund, Trine Meldgaard ; Holst, Helle</creator><creatorcontrib>Gade, Christina ; Sverrisdóttir, Eva ; Dalhoff, Kim ; Sonne, Jesper ; Johansen, Mia Østergaard ; Christensen, Hanne Rolighed ; Burhenne, Jürgen ; Mikus, Gerd ; Holm, Jens Christian ; Lund, Trine Meldgaard ; Holst, Helle</creatorcontrib><description>Background
Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.
Objective
The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11–18 years.
Methods
All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration–time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters.
Results
Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations.
Conclusions
The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity.
Trial registration
EudraCT: 2014-004554-34.</description><identifier>ISSN: 0312-5963</identifier><identifier>EISSN: 1179-1926</identifier><identifier>DOI: 10.1007/s40262-019-00838-1</identifier><identifier>PMID: 31745864</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Age ; Body mass index ; Children & youth ; Cytochrome ; Drug dosages ; Internal Medicine ; Liver diseases ; Medicine ; Medicine & Public Health ; Metabolic syndrome ; Obesity ; Original Research Article ; Pediatrics ; Pharmacokinetics ; Pharmacology/Toxicology ; Pharmacotherapy ; Plasma ; Population ; Studies ; Teenagers</subject><ispartof>Clinical pharmacokinetics, 2020-05, Vol.59 (5), p.643-654</ispartof><rights>Springer Nature Switzerland AG 2019</rights><rights>Copyright Springer Nature B.V. May 2020</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-12013f92a04e02613d24e921f21746586c681c39a72a5b54a1301c19be85bf643</citedby><cites>FETCH-LOGICAL-c441t-12013f92a04e02613d24e921f21746586c681c39a72a5b54a1301c19be85bf643</cites><orcidid>0000-0002-0007-6158</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s40262-019-00838-1$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s40262-019-00838-1$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31745864$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gade, Christina</creatorcontrib><creatorcontrib>Sverrisdóttir, Eva</creatorcontrib><creatorcontrib>Dalhoff, Kim</creatorcontrib><creatorcontrib>Sonne, Jesper</creatorcontrib><creatorcontrib>Johansen, Mia Østergaard</creatorcontrib><creatorcontrib>Christensen, Hanne Rolighed</creatorcontrib><creatorcontrib>Burhenne, Jürgen</creatorcontrib><creatorcontrib>Mikus, Gerd</creatorcontrib><creatorcontrib>Holm, Jens Christian</creatorcontrib><creatorcontrib>Lund, Trine Meldgaard</creatorcontrib><creatorcontrib>Holst, Helle</creatorcontrib><title>Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents</title><title>Clinical pharmacokinetics</title><addtitle>Clin Pharmacokinet</addtitle><addtitle>Clin Pharmacokinet</addtitle><description>Background
Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.
Objective
The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11–18 years.
Methods
All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration–time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters.
Results
Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations.
Conclusions
The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity.
Trial registration
EudraCT: 2014-004554-34.</description><subject>Age</subject><subject>Body mass index</subject><subject>Children & youth</subject><subject>Cytochrome</subject><subject>Drug dosages</subject><subject>Internal Medicine</subject><subject>Liver diseases</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic syndrome</subject><subject>Obesity</subject><subject>Original Research Article</subject><subject>Pediatrics</subject><subject>Pharmacokinetics</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacotherapy</subject><subject>Plasma</subject><subject>Population</subject><subject>Studies</subject><subject>Teenagers</subject><issn>0312-5963</issn><issn>1179-1926</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNp9kMtOwzAQRS0EoqXwAyxQJNYGj-08vKwqniqUBawtx3FoSmIXO13A12OaAjtW1nju3LlzEDoFcgGE5JeBE5pRTEBgQgpWYNhDY4BcYBA020djwoDiVGRshI5CWJGoooQcohGDnKdFxsfo_qGp1KdrVZc8LZXvlHZvjTV9o0PS2GRRmmASZavk0VnsttVs2bSVN3b7Pa1ca4I2tg_H6KBWbTAnu3eCXq6vnme3eL64uZtN51hzDj0GSoDVgirCTcwPrKLcCAo1jaGymEpnBWgmVE5VWqZcASOgQZSmSMs642yCzgfftXfvGxN6uXIbb-NKSTnhTHCIJ08QHVTauxC8qeXaN53yHxKI_MYnB3wy4pNbfBLi0NnOelN2pvod-eEVBWwQhNiyr8b_7f7H9gvzE3hQ</recordid><startdate>20200501</startdate><enddate>20200501</enddate><creator>Gade, Christina</creator><creator>Sverrisdóttir, Eva</creator><creator>Dalhoff, Kim</creator><creator>Sonne, Jesper</creator><creator>Johansen, Mia Østergaard</creator><creator>Christensen, Hanne Rolighed</creator><creator>Burhenne, Jürgen</creator><creator>Mikus, Gerd</creator><creator>Holm, Jens Christian</creator><creator>Lund, Trine Meldgaard</creator><creator>Holst, Helle</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>4T-</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</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>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><orcidid>https://orcid.org/0000-0002-0007-6158</orcidid></search><sort><creationdate>20200501</creationdate><title>Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents</title><author>Gade, Christina ; Sverrisdóttir, Eva ; Dalhoff, Kim ; Sonne, Jesper ; Johansen, Mia Østergaard ; Christensen, Hanne Rolighed ; Burhenne, Jürgen ; Mikus, Gerd ; Holm, Jens Christian ; Lund, Trine Meldgaard ; Holst, Helle</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-12013f92a04e02613d24e921f21746586c681c39a72a5b54a1301c19be85bf643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Age</topic><topic>Body mass index</topic><topic>Children & youth</topic><topic>Cytochrome</topic><topic>Drug dosages</topic><topic>Internal Medicine</topic><topic>Liver diseases</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic syndrome</topic><topic>Obesity</topic><topic>Original Research Article</topic><topic>Pediatrics</topic><topic>Pharmacokinetics</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacotherapy</topic><topic>Plasma</topic><topic>Population</topic><topic>Studies</topic><topic>Teenagers</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gade, Christina</creatorcontrib><creatorcontrib>Sverrisdóttir, Eva</creatorcontrib><creatorcontrib>Dalhoff, Kim</creatorcontrib><creatorcontrib>Sonne, Jesper</creatorcontrib><creatorcontrib>Johansen, Mia Østergaard</creatorcontrib><creatorcontrib>Christensen, Hanne Rolighed</creatorcontrib><creatorcontrib>Burhenne, Jürgen</creatorcontrib><creatorcontrib>Mikus, Gerd</creatorcontrib><creatorcontrib>Holm, Jens Christian</creatorcontrib><creatorcontrib>Lund, Trine Meldgaard</creatorcontrib><creatorcontrib>Holst, Helle</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Docstoc</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</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>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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><jtitle>Clinical pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gade, Christina</au><au>Sverrisdóttir, Eva</au><au>Dalhoff, Kim</au><au>Sonne, Jesper</au><au>Johansen, Mia Østergaard</au><au>Christensen, Hanne Rolighed</au><au>Burhenne, Jürgen</au><au>Mikus, Gerd</au><au>Holm, Jens Christian</au><au>Lund, Trine Meldgaard</au><au>Holst, Helle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents</atitle><jtitle>Clinical pharmacokinetics</jtitle><stitle>Clin Pharmacokinet</stitle><addtitle>Clin Pharmacokinet</addtitle><date>2020-05-01</date><risdate>2020</risdate><volume>59</volume><issue>5</issue><spage>643</spage><epage>654</epage><pages>643-654</pages><issn>0312-5963</issn><eissn>1179-1926</eissn><abstract>Background
Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient.
Objective
The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11–18 years.
Methods
All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration–time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters.
Results
Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations.
Conclusions
The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity.
Trial registration
EudraCT: 2014-004554-34.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>31745864</pmid><doi>10.1007/s40262-019-00838-1</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-0007-6158</orcidid></addata></record> |
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| ispartof | Clinical pharmacokinetics, 2020-05, Vol.59 (5), p.643-654 |
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| language | eng |
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| source | SpringerNature Journals |
| subjects | Age Body mass index Children & youth Cytochrome Drug dosages Internal Medicine Liver diseases Medicine Medicine & Public Health Metabolic syndrome Obesity Original Research Article Pediatrics Pharmacokinetics Pharmacology/Toxicology Pharmacotherapy Plasma Population Studies Teenagers |
| title | Midazolam Pharmacokinetics in Obese and Non-obese Children and Adolescents |
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