A pharmacokinetic model for voriconazole in a highly diversified population of children and adolescents with cancer
Summary Background The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure. Objectives To create a pharmacokinetic model that could help to explain the variability. Methods Retrospective review of paediatric patients with cancer. Models were built using...
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| Veröffentlicht in: | Mycoses 2019-04, Vol.62 (4), p.399-404 |
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| container_title | Mycoses |
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| creator | Carlesse, Fabianne Altruda de Moraes Costa Araujo, Orlei Ribeiro Marques, Leticia Maria Acioli Silva, Dafne Cardoso Bourguignon da Senerchia, Andreza Almeida Petrilli, Antonio Sergio |
| description | Summary
Background
The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure.
Objectives
To create a pharmacokinetic model that could help to explain the variability.
Methods
Retrospective review of paediatric patients with cancer. Models were built using Pmetrics.
Results
We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations |
| doi_str_mv | 10.1111/myc.12899 |
| format | Article |
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Background
The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure.
Objectives
To create a pharmacokinetic model that could help to explain the variability.
Methods
Retrospective review of paediatric patients with cancer. Models were built using Pmetrics.
Results
We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations <1 mg/L and death attributable to fungal disease. Bioavailability was estimated in 50%. The maximum velocity of clearance was reduced in deceased patients.
Conclusions
Extremely ill patients can be poor metabolizers of voriconazole. Therapeutic monitoring promotes only a limited improvement in drug management.</description><identifier>ISSN: 0933-7407</identifier><identifier>EISSN: 1439-0507</identifier><identifier>DOI: 10.1111/myc.12899</identifier><identifier>PMID: 30687957</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Adolescent ; Adolescents ; Antifungal Agents - administration & dosage ; Antifungal Agents - pharmacokinetics ; Bioavailability ; Cancer ; Child ; children ; Dosage ; Female ; Humans ; Invasiveness ; Male ; Mycoses - drug therapy ; Neoplasms - complications ; Pharmacokinetics ; Retrospective Studies ; Serum levels ; Voriconazole ; Voriconazole - administration & dosage ; Voriconazole - pharmacokinetics</subject><ispartof>Mycoses, 2019-04, Vol.62 (4), p.399-404</ispartof><rights>2019 Blackwell Verlag GmbH</rights><rights>2019 Blackwell Verlag GmbH.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3539-bec9b32a5190d1d5b131adcdcaec7f8bca3323cf655a84738637cb2c5823e6b83</citedby><cites>FETCH-LOGICAL-c3539-bec9b32a5190d1d5b131adcdcaec7f8bca3323cf655a84738637cb2c5823e6b83</cites><orcidid>0000-0001-8230-6801</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fmyc.12899$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fmyc.12899$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30687957$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Carlesse, Fabianne Altruda de Moraes Costa</creatorcontrib><creatorcontrib>Araujo, Orlei Ribeiro</creatorcontrib><creatorcontrib>Marques, Leticia Maria Acioli</creatorcontrib><creatorcontrib>Silva, Dafne Cardoso Bourguignon da</creatorcontrib><creatorcontrib>Senerchia, Andreza Almeida</creatorcontrib><creatorcontrib>Petrilli, Antonio Sergio</creatorcontrib><title>A pharmacokinetic model for voriconazole in a highly diversified population of children and adolescents with cancer</title><title>Mycoses</title><addtitle>Mycoses</addtitle><description>Summary
Background
The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure.
Objectives
To create a pharmacokinetic model that could help to explain the variability.
Methods
Retrospective review of paediatric patients with cancer. Models were built using Pmetrics.
Results
We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations <1 mg/L and death attributable to fungal disease. Bioavailability was estimated in 50%. The maximum velocity of clearance was reduced in deceased patients.
Conclusions
Extremely ill patients can be poor metabolizers of voriconazole. Therapeutic monitoring promotes only a limited improvement in drug management.</description><subject>Adolescent</subject><subject>Adolescents</subject><subject>Antifungal Agents - administration & dosage</subject><subject>Antifungal Agents - pharmacokinetics</subject><subject>Bioavailability</subject><subject>Cancer</subject><subject>Child</subject><subject>children</subject><subject>Dosage</subject><subject>Female</subject><subject>Humans</subject><subject>Invasiveness</subject><subject>Male</subject><subject>Mycoses - drug therapy</subject><subject>Neoplasms - complications</subject><subject>Pharmacokinetics</subject><subject>Retrospective Studies</subject><subject>Serum levels</subject><subject>Voriconazole</subject><subject>Voriconazole - administration & dosage</subject><subject>Voriconazole - pharmacokinetics</subject><issn>0933-7407</issn><issn>1439-0507</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kD1PwzAQQC0EoqUw8AeQJSaGtnZcx_FYVXxJRSwwMEXO2SEuSRzstFX59RgKbHi55d07-SF0TsmExjdtdjChSSblARrSGZNjwok4REMiGRuLGREDdBLCihAqZJIeowEjaSYkF0MU5rirlG8UuDfbmt4Cbpw2NS6dxxvnLbhWfbjaYNtihSv7WtU7rO3G-GBLazTuXLeuVW9di12JobK19iayrcZKx8UApu0D3tq-wqBaMP4UHZWqDubsZ47Q88310-JuvHy8vV_Ml2NgPH6iMCALlihOJdFU84IyqjRoUAZEmRWgGEsYlCnnKpsJlqVMQJEAzxJm0iJjI3S593beva9N6POVW_s2nswTKjNOeEpZpK72FHgXgjdl3nnbKL_LKcm_8uYxb_6dN7IXP8Z10Rj9R_72jMB0D2xtbXb_m_KHl8Ve-QmwUoaE</recordid><startdate>201904</startdate><enddate>201904</enddate><creator>Carlesse, Fabianne Altruda de Moraes Costa</creator><creator>Araujo, Orlei Ribeiro</creator><creator>Marques, Leticia Maria Acioli</creator><creator>Silva, Dafne Cardoso Bourguignon da</creator><creator>Senerchia, Andreza Almeida</creator><creator>Petrilli, Antonio Sergio</creator><general>Wiley Subscription Services, 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>M7N</scope><orcidid>https://orcid.org/0000-0001-8230-6801</orcidid></search><sort><creationdate>201904</creationdate><title>A pharmacokinetic model for voriconazole in a highly diversified population of children and adolescents with cancer</title><author>Carlesse, Fabianne Altruda de Moraes Costa ; Araujo, Orlei Ribeiro ; Marques, Leticia Maria Acioli ; Silva, Dafne Cardoso Bourguignon da ; Senerchia, Andreza Almeida ; Petrilli, Antonio Sergio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3539-bec9b32a5190d1d5b131adcdcaec7f8bca3323cf655a84738637cb2c5823e6b83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adolescent</topic><topic>Adolescents</topic><topic>Antifungal Agents - administration & dosage</topic><topic>Antifungal Agents - pharmacokinetics</topic><topic>Bioavailability</topic><topic>Cancer</topic><topic>Child</topic><topic>children</topic><topic>Dosage</topic><topic>Female</topic><topic>Humans</topic><topic>Invasiveness</topic><topic>Male</topic><topic>Mycoses - drug therapy</topic><topic>Neoplasms - complications</topic><topic>Pharmacokinetics</topic><topic>Retrospective Studies</topic><topic>Serum levels</topic><topic>Voriconazole</topic><topic>Voriconazole - administration & dosage</topic><topic>Voriconazole - pharmacokinetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Carlesse, Fabianne Altruda de Moraes Costa</creatorcontrib><creatorcontrib>Araujo, Orlei Ribeiro</creatorcontrib><creatorcontrib>Marques, Leticia Maria Acioli</creatorcontrib><creatorcontrib>Silva, Dafne Cardoso Bourguignon da</creatorcontrib><creatorcontrib>Senerchia, Andreza Almeida</creatorcontrib><creatorcontrib>Petrilli, Antonio Sergio</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><jtitle>Mycoses</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Carlesse, Fabianne Altruda de Moraes Costa</au><au>Araujo, Orlei Ribeiro</au><au>Marques, Leticia Maria Acioli</au><au>Silva, Dafne Cardoso Bourguignon da</au><au>Senerchia, Andreza Almeida</au><au>Petrilli, Antonio Sergio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A pharmacokinetic model for voriconazole in a highly diversified population of children and adolescents with cancer</atitle><jtitle>Mycoses</jtitle><addtitle>Mycoses</addtitle><date>2019-04</date><risdate>2019</risdate><volume>62</volume><issue>4</issue><spage>399</spage><epage>404</epage><pages>399-404</pages><issn>0933-7407</issn><eissn>1439-0507</eissn><abstract>Summary
Background
The wide pharmacokinetic variability of voriconazole leads to uncertainty regarding adequate exposure.
Objectives
To create a pharmacokinetic model that could help to explain the variability.
Methods
Retrospective review of paediatric patients with cancer. Models were built using Pmetrics.
Results
We analysed 158 trough measurements in 55 patients; in 41.8%, the serum levels were between 1 and 6 mg/L on initial measurement. After the measurements, dosage adjustments were made in 42 (76.3%) patients, and the percentage of adequate levels rose to 54.5%. Fourteen deaths (25.4%) were attributed to invasive fungal diseases. The mean serum levels were higher in deceased patients (mean ± SD: 3.1 ± 3.2 mg/L vs 2.5 ± 3.6 mg/L in survivors; P = 0.018), but the median doses per kg were higher in survivors. Drug exposure was also higher in deceased patients (mean ± SD of AUC: 19.2 ± 8.1 vs 9.5 ± 19.1 in survivors; P = 0.005). No correlation was found between serum concentrations <1 mg/L and death attributable to fungal disease. Bioavailability was estimated in 50%. The maximum velocity of clearance was reduced in deceased patients.
Conclusions
Extremely ill patients can be poor metabolizers of voriconazole. Therapeutic monitoring promotes only a limited improvement in drug management.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>30687957</pmid><doi>10.1111/myc.12899</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0001-8230-6801</orcidid></addata></record> |
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| ispartof | Mycoses, 2019-04, Vol.62 (4), p.399-404 |
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| language | eng |
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| source | MEDLINE; Wiley Online Library Journals Frontfile Complete |
| subjects | Adolescent Adolescents Antifungal Agents - administration & dosage Antifungal Agents - pharmacokinetics Bioavailability Cancer Child children Dosage Female Humans Invasiveness Male Mycoses - drug therapy Neoplasms - complications Pharmacokinetics Retrospective Studies Serum levels Voriconazole Voriconazole - administration & dosage Voriconazole - pharmacokinetics |
| title | A pharmacokinetic model for voriconazole in a highly diversified population of children and adolescents with cancer |
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