Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid
Aims Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasm...
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Veröffentlicht in: | British journal of clinical pharmacology 2016-06, Vol.81 (6), p.1113-1123 |
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container_title | British journal of clinical pharmacology |
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creator | Hasselt, J. G. Coen Rizk, Matthew L. Lala, Mallika Chavez‐Eng, Cynthia Visser, Sandra A. G. Kerbusch, Thomas Danhof, Meindert Rao, Gauri Graaf, Piet H. |
description | Aims
Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration.
Methods
A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter‐individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration.
Results
A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter‐compartmental clearance were 11.5 l h–1, 9.37 l, 6.41 l, 13.7 l h–1, respectively (relative standard error (RSE) |
doi_str_mv | 10.1111/bcp.12901 |
format | Article |
fullrecord | <record><control><sourceid>wiley_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4876184</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>BCP12901</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4151-b92e450f780d384df58e102c0bb07dc4b32af9b0aa08545e2bb71224ec35fdae3</originalsourceid><addsrcrecordid>eNp1kMlOwzAQhi0EomU58ALIVw5pbSdO0gsSVGxSJXqAs-Vl0hocO8oC6ttjKFRwwJexZr75RvoROqNkQuObKt1MKJsRuofGNM15wijj-2hMUpInnHE6Qkdd90IITWnOD9GI5SVnrCjGSC1DcGBwE5rByd4Gj5u1bGupw6v10FuN62DA4VBhW9sGPNTYRsjJrpZYeoP7NWA3-BWGxsa_s9JhZ72NncoN1pygg0q6Dk6_6zF6vr15mt8ni8e7h_nVItEZ5TRRMwYZJ1VREpOWmal4CZQwTZQihdGZSpmsZopISUqecWBKFZSxDHTKKyMhPUaXW28zqBqMBt-30ommtbVsNyJIK_5OvF2LVXgTWVnktMyi4GIr0G3ouhaq3S4l4jNoEYMWX0FH9vz3sR35k2wEplvg3TrY_G8S1_PlVvkBh_KKpA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Wiley Online Library (Open Access Collection)</source><creator>Hasselt, J. G. Coen ; Rizk, Matthew L. ; Lala, Mallika ; Chavez‐Eng, Cynthia ; Visser, Sandra A. G. ; Kerbusch, Thomas ; Danhof, Meindert ; Rao, Gauri ; Graaf, Piet H.</creator><creatorcontrib>Hasselt, J. G. Coen ; Rizk, Matthew L. ; Lala, Mallika ; Chavez‐Eng, Cynthia ; Visser, Sandra A. G. ; Kerbusch, Thomas ; Danhof, Meindert ; Rao, Gauri ; Graaf, Piet H.</creatorcontrib><description>Aims
Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration.
Methods
A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter‐individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration.
Results
A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter‐compartmental clearance were 11.5 l h–1, 9.37 l, 6.41 l, 13.7 l h–1, respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time‐independent penetration coefficient of 0.44 (RSE 14%).
Conclusion
The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups.</description><identifier>ISSN: 0306-5251</identifier><identifier>EISSN: 1365-2125</identifier><identifier>DOI: 10.1111/bcp.12901</identifier><identifier>PMID: 26852277</identifier><language>eng</language><publisher>England: John Wiley and Sons Inc</publisher><subject>Adolescent ; Adult ; Aged ; antibiotics ; Bronchoalveolar Lavage Fluid - chemistry ; epithelial lining fluid ; Female ; Healthy Volunteers ; Humans ; imipenem ; Imipenem - analysis ; Imipenem - blood ; Imipenem - pharmacokinetics ; lung ; Lung - metabolism ; Male ; Meta-Analysis as Topic ; Middle Aged ; Models, Biological ; Pharmacokinetics ; Renal Insufficiency - metabolism ; Young Adult</subject><ispartof>British journal of clinical pharmacology, 2016-06, Vol.81 (6), p.1113-1123</ispartof><rights>2016 The British Pharmacological Society</rights><rights>2016 The British Pharmacological Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4151-b92e450f780d384df58e102c0bb07dc4b32af9b0aa08545e2bb71224ec35fdae3</citedby><cites>FETCH-LOGICAL-c4151-b92e450f780d384df58e102c0bb07dc4b32af9b0aa08545e2bb71224ec35fdae3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fbcp.12901$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fbcp.12901$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,1433,27924,27925,45574,45575,46409,46833</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26852277$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hasselt, J. G. Coen</creatorcontrib><creatorcontrib>Rizk, Matthew L.</creatorcontrib><creatorcontrib>Lala, Mallika</creatorcontrib><creatorcontrib>Chavez‐Eng, Cynthia</creatorcontrib><creatorcontrib>Visser, Sandra A. G.</creatorcontrib><creatorcontrib>Kerbusch, Thomas</creatorcontrib><creatorcontrib>Danhof, Meindert</creatorcontrib><creatorcontrib>Rao, Gauri</creatorcontrib><creatorcontrib>Graaf, Piet H.</creatorcontrib><title>Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid</title><title>British journal of clinical pharmacology</title><addtitle>Br J Clin Pharmacol</addtitle><description>Aims
Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration.
Methods
A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter‐individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration.
Results
A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter‐compartmental clearance were 11.5 l h–1, 9.37 l, 6.41 l, 13.7 l h–1, respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time‐independent penetration coefficient of 0.44 (RSE 14%).
Conclusion
The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>antibiotics</subject><subject>Bronchoalveolar Lavage Fluid - chemistry</subject><subject>epithelial lining fluid</subject><subject>Female</subject><subject>Healthy Volunteers</subject><subject>Humans</subject><subject>imipenem</subject><subject>Imipenem - analysis</subject><subject>Imipenem - blood</subject><subject>Imipenem - pharmacokinetics</subject><subject>lung</subject><subject>Lung - metabolism</subject><subject>Male</subject><subject>Meta-Analysis as Topic</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Pharmacokinetics</subject><subject>Renal Insufficiency - metabolism</subject><subject>Young Adult</subject><issn>0306-5251</issn><issn>1365-2125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMlOwzAQhi0EomU58ALIVw5pbSdO0gsSVGxSJXqAs-Vl0hocO8oC6ttjKFRwwJexZr75RvoROqNkQuObKt1MKJsRuofGNM15wijj-2hMUpInnHE6Qkdd90IITWnOD9GI5SVnrCjGSC1DcGBwE5rByd4Gj5u1bGupw6v10FuN62DA4VBhW9sGPNTYRsjJrpZYeoP7NWA3-BWGxsa_s9JhZ72NncoN1pygg0q6Dk6_6zF6vr15mt8ni8e7h_nVItEZ5TRRMwYZJ1VREpOWmal4CZQwTZQihdGZSpmsZopISUqecWBKFZSxDHTKKyMhPUaXW28zqBqMBt-30ommtbVsNyJIK_5OvF2LVXgTWVnktMyi4GIr0G3ouhaq3S4l4jNoEYMWX0FH9vz3sR35k2wEplvg3TrY_G8S1_PlVvkBh_KKpA</recordid><startdate>201606</startdate><enddate>201606</enddate><creator>Hasselt, J. G. Coen</creator><creator>Rizk, Matthew L.</creator><creator>Lala, Mallika</creator><creator>Chavez‐Eng, Cynthia</creator><creator>Visser, Sandra A. G.</creator><creator>Kerbusch, Thomas</creator><creator>Danhof, Meindert</creator><creator>Rao, Gauri</creator><creator>Graaf, Piet H.</creator><general>John Wiley and Sons Inc</general><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>5PM</scope></search><sort><creationdate>201606</creationdate><title>Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid</title><author>Hasselt, J. G. Coen ; Rizk, Matthew L. ; Lala, Mallika ; Chavez‐Eng, Cynthia ; Visser, Sandra A. G. ; Kerbusch, Thomas ; Danhof, Meindert ; Rao, Gauri ; Graaf, Piet H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4151-b92e450f780d384df58e102c0bb07dc4b32af9b0aa08545e2bb71224ec35fdae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>antibiotics</topic><topic>Bronchoalveolar Lavage Fluid - chemistry</topic><topic>epithelial lining fluid</topic><topic>Female</topic><topic>Healthy Volunteers</topic><topic>Humans</topic><topic>imipenem</topic><topic>Imipenem - analysis</topic><topic>Imipenem - blood</topic><topic>Imipenem - pharmacokinetics</topic><topic>lung</topic><topic>Lung - metabolism</topic><topic>Male</topic><topic>Meta-Analysis as Topic</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Pharmacokinetics</topic><topic>Renal Insufficiency - metabolism</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hasselt, J. G. Coen</creatorcontrib><creatorcontrib>Rizk, Matthew L.</creatorcontrib><creatorcontrib>Lala, Mallika</creatorcontrib><creatorcontrib>Chavez‐Eng, Cynthia</creatorcontrib><creatorcontrib>Visser, Sandra A. G.</creatorcontrib><creatorcontrib>Kerbusch, Thomas</creatorcontrib><creatorcontrib>Danhof, Meindert</creatorcontrib><creatorcontrib>Rao, Gauri</creatorcontrib><creatorcontrib>Graaf, Piet H.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hasselt, J. G. Coen</au><au>Rizk, Matthew L.</au><au>Lala, Mallika</au><au>Chavez‐Eng, Cynthia</au><au>Visser, Sandra A. G.</au><au>Kerbusch, Thomas</au><au>Danhof, Meindert</au><au>Rao, Gauri</au><au>Graaf, Piet H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid</atitle><jtitle>British journal of clinical pharmacology</jtitle><addtitle>Br J Clin Pharmacol</addtitle><date>2016-06</date><risdate>2016</risdate><volume>81</volume><issue>6</issue><spage>1113</spage><epage>1123</epage><pages>1113-1123</pages><issn>0306-5251</issn><eissn>1365-2125</eissn><abstract>Aims
Several clinical trials have confirmed the therapeutic benefit of imipenem for treatment of lung infections. There is however no knowledge of the penetration of imipenem into the lung epithelial lining fluid (ELF), the site of action relevant for lung infections. Furthermore, although the plasma pharmacokinetics (PK) of imipenem has been widely studied, most studies have been based on selected patient groups. The aim of this analysis was to characterize imipenem plasma PK across populations and to quantify imipenem ELF penetration.
Methods
A population model for imipenem plasma PK was developed using data obtained from healthy volunteers, elderly subjects and subjects with renal impairment, in order to identify predictors for inter‐individual variability (IIV) of imipenem PK. Subsequently, a clinical study which measured plasma and ELF concentrations of imipenem was included in order to quantify lung penetration.
Results
A two compartmental model best described the plasma PK of imipenem. Creatinine clearance and body weight were included as subject characteristics predictive for IIV on clearance. Typical estimates for clearance, central and peripheral volume, and inter‐compartmental clearance were 11.5 l h–1, 9.37 l, 6.41 l, 13.7 l h–1, respectively (relative standard error (RSE) <8%). The distribution of imipenem into ELF was described using a time‐independent penetration coefficient of 0.44 (RSE 14%).
Conclusion
The identified lung penetration coefficient confirms the clinical relevance of imipenem for treatment of lung infections, while the population PK model provided insights into predictors of IIV for imipenem PK and may be of relevance to support dose optimization in various subject groups.</abstract><cop>England</cop><pub>John Wiley and Sons Inc</pub><pmid>26852277</pmid><doi>10.1111/bcp.12901</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adolescent Adult Aged antibiotics Bronchoalveolar Lavage Fluid - chemistry epithelial lining fluid Female Healthy Volunteers Humans imipenem Imipenem - analysis Imipenem - blood Imipenem - pharmacokinetics lung Lung - metabolism Male Meta-Analysis as Topic Middle Aged Models, Biological Pharmacokinetics Renal Insufficiency - metabolism Young Adult |
title | Pooled population pharmacokinetic model of imipenem in plasma and the lung epithelial lining fluid |
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