Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice
Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were eval...
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| Veröffentlicht in: | Antimicrobial agents and chemotherapy 2015-10, Vol.59 (10), p.6344-6351 |
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| creator | Smits, A De Cock, R F W Allegaert, K Vanhaesebrouck, S Danhof, M Knibbe, C A J |
| description | Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were 24 mg/liter were reached at steady state in almost all patients. Trough values of |
| doi_str_mv | 10.1128/AAC.01157-15 |
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The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.</description><identifier>ISSN: 0066-4804</identifier><identifier>EISSN: 1098-6596</identifier><identifier>DOI: 10.1128/AAC.01157-15</identifier><identifier>PMID: 26248375</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>Amikacin ; Amikacin - blood ; Amikacin - pharmacokinetics ; Amikacin - pharmacology ; Anti-Bacterial Agents ; Anti-Bacterial Agents - blood ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - pharmacology ; Birth Weight ; Creatinine - blood ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drug Monitoring ; Female ; Gestational Age ; Humans ; Infant ; Infant, Newborn ; Infant, Premature ; Male ; Models, Statistical ; Monte Carlo Method ; Pharmacology ; Precision Medicine ; Prospective Studies ; Sepsis - drug therapy ; Sepsis - microbiology ; Sepsis - pathology</subject><ispartof>Antimicrobial agents and chemotherapy, 2015-10, Vol.59 (10), p.6344-6351</ispartof><rights>Copyright © 2015, American Society for Microbiology. All Rights Reserved.</rights><rights>Copyright © 2015, American Society for Microbiology. All Rights Reserved. 2015 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a418t-b9f6484827b054fa1dc99c8b8106ba7e5f7aed6576cde4ad24673dc78fc169913</citedby><cites>FETCH-LOGICAL-a418t-b9f6484827b054fa1dc99c8b8106ba7e5f7aed6576cde4ad24673dc78fc169913</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576045/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576045/$$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/26248375$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smits, A</creatorcontrib><creatorcontrib>De Cock, R F W</creatorcontrib><creatorcontrib>Allegaert, K</creatorcontrib><creatorcontrib>Vanhaesebrouck, S</creatorcontrib><creatorcontrib>Danhof, M</creatorcontrib><creatorcontrib>Knibbe, C A J</creatorcontrib><title>Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice</title><title>Antimicrobial agents and chemotherapy</title><addtitle>Antimicrob Agents Chemother</addtitle><addtitle>Antimicrob Agents Chemother</addtitle><description>Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.</description><subject>Amikacin</subject><subject>Amikacin - blood</subject><subject>Amikacin - pharmacokinetics</subject><subject>Amikacin - pharmacology</subject><subject>Anti-Bacterial Agents</subject><subject>Anti-Bacterial Agents - blood</subject><subject>Anti-Bacterial Agents - pharmacokinetics</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Birth Weight</subject><subject>Creatinine - blood</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Administration Schedule</subject><subject>Drug Monitoring</subject><subject>Female</subject><subject>Gestational Age</subject><subject>Humans</subject><subject>Infant</subject><subject>Infant, Newborn</subject><subject>Infant, Premature</subject><subject>Male</subject><subject>Models, Statistical</subject><subject>Monte Carlo Method</subject><subject>Pharmacology</subject><subject>Precision Medicine</subject><subject>Prospective Studies</subject><subject>Sepsis - drug therapy</subject><subject>Sepsis - microbiology</subject><subject>Sepsis - pathology</subject><issn>0066-4804</issn><issn>1098-6596</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU2LFDEQhoMo7rh68yw5Kthr0p1OJxdhHNcPWHWR9Ryqk-oxa3cym3QP-O_NOOuiByGQhHp4iqqXkKecnXFeq1fr9eaMcd52FW_vkRVnWlWy1fI-WTEmZSUUEyfkUc7XrPxbzR6Sk1rWQjVduyLLZYp5h3b2e6TnexgXmH0MNA4U6KfocKzeQEZH38bsw5Z-xa2fMNAhJrqe_A-wPtByLhPOmCYKwdGrw-MzxgAz5kNxM_rgLYyFgtLJ4mPyYIAx45Pb-5R8e3d-tflQXXx5_3GzvqhAcDVXvR6kUELVXc9aMQB3VmuresWZ7KHDdugAnWw7aR0KcLWQXeNspwbLpda8OSWvj97d0k_oLIY5wWh2yU-QfpoI3vxbCf672ca9EcXJRFsEz28FKd4smGcz-WxxHCFgXLLhHW-00LVsCvryiNqy0ZxwuGvDmTkkZUpS5ndShh_ML4445Kk213FJoWzif-yzv8e4E_-JsfkF2KScdA</recordid><startdate>20151001</startdate><enddate>20151001</enddate><creator>Smits, A</creator><creator>De Cock, R F W</creator><creator>Allegaert, K</creator><creator>Vanhaesebrouck, S</creator><creator>Danhof, M</creator><creator>Knibbe, C A J</creator><general>American Society for Microbiology</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20151001</creationdate><title>Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice</title><author>Smits, A ; De Cock, R F W ; Allegaert, K ; Vanhaesebrouck, S ; Danhof, M ; Knibbe, C A J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a418t-b9f6484827b054fa1dc99c8b8106ba7e5f7aed6576cde4ad24673dc78fc169913</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amikacin</topic><topic>Amikacin - blood</topic><topic>Amikacin - pharmacokinetics</topic><topic>Amikacin - pharmacology</topic><topic>Anti-Bacterial Agents</topic><topic>Anti-Bacterial Agents - blood</topic><topic>Anti-Bacterial Agents - pharmacokinetics</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Birth Weight</topic><topic>Creatinine - blood</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Administration Schedule</topic><topic>Drug Monitoring</topic><topic>Female</topic><topic>Gestational Age</topic><topic>Humans</topic><topic>Infant</topic><topic>Infant, Newborn</topic><topic>Infant, Premature</topic><topic>Male</topic><topic>Models, Statistical</topic><topic>Monte Carlo Method</topic><topic>Pharmacology</topic><topic>Precision Medicine</topic><topic>Prospective Studies</topic><topic>Sepsis - drug therapy</topic><topic>Sepsis - microbiology</topic><topic>Sepsis - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smits, A</creatorcontrib><creatorcontrib>De Cock, R F W</creatorcontrib><creatorcontrib>Allegaert, K</creatorcontrib><creatorcontrib>Vanhaesebrouck, S</creatorcontrib><creatorcontrib>Danhof, M</creatorcontrib><creatorcontrib>Knibbe, C A J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Antimicrobial agents and chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smits, A</au><au>De Cock, R F W</au><au>Allegaert, K</au><au>Vanhaesebrouck, S</au><au>Danhof, M</au><au>Knibbe, C A J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice</atitle><jtitle>Antimicrobial agents and chemotherapy</jtitle><stitle>Antimicrob Agents Chemother</stitle><addtitle>Antimicrob Agents Chemother</addtitle><date>2015-10-01</date><risdate>2015</risdate><volume>59</volume><issue>10</issue><spage>6344</spage><epage>6351</epage><pages>6344-6351</pages><issn>0066-4804</issn><eissn>1098-6596</eissn><abstract>Based on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>26248375</pmid><doi>10.1128/AAC.01157-15</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Amikacin Amikacin - blood Amikacin - pharmacokinetics Amikacin - pharmacology Anti-Bacterial Agents Anti-Bacterial Agents - blood Anti-Bacterial Agents - pharmacokinetics Anti-Bacterial Agents - pharmacology Birth Weight Creatinine - blood Dose-Response Relationship, Drug Drug Administration Schedule Drug Monitoring Female Gestational Age Humans Infant Infant, Newborn Infant, Premature Male Models, Statistical Monte Carlo Method Pharmacology Precision Medicine Prospective Studies Sepsis - drug therapy Sepsis - microbiology Sepsis - pathology |
| title | Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice |
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