Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort
The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD. As a single-centre pilot study, 19...
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| Veröffentlicht in: | Journal of antimicrobial chemotherapy 2015-04, Vol.70 (4), p.1161-1165 |
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| creator | Trubiano, J A Crowe, A Worth, L J Thursky, K A Slavin, M A |
| description | The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD.
As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured.
The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels |
| doi_str_mv | 10.1093/jac/dku529 |
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As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured.
The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%).
Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.</description><identifier>ISSN: 0305-7453</identifier><identifier>EISSN: 1460-2091</identifier><identifier>DOI: 10.1093/jac/dku529</identifier><identifier>PMID: 25558073</identifier><language>eng</language><publisher>England: Oxford Publishing Limited (England)</publisher><subject>Aged ; Antibiotics ; Antifungal Agents - adverse effects ; Antifungal Agents - therapeutic use ; Cohort Studies ; Cytochrome P-450 CYP2C19 - genetics ; Drug therapy ; Female ; Fungal infections ; Genomics ; Genotyping Techniques ; Hematologic Neoplasms - complications ; Humans ; Male ; Middle Aged ; Mycoses - drug therapy ; Patients ; Pharmacogenetics - methods ; Pharmacology ; Pilot Projects ; Treatment Outcome ; Voriconazole - adverse effects ; Voriconazole - therapeutic use</subject><ispartof>Journal of antimicrobial chemotherapy, 2015-04, Vol.70 (4), p.1161-1165</ispartof><rights>The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.</rights><rights>Copyright Oxford Publishing Limited(England) Apr 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c281t-b34927a44bf04b4efac76dfce22730b398a87b39cce40e9875b5c0984eecdf963</citedby><cites>FETCH-LOGICAL-c281t-b34927a44bf04b4efac76dfce22730b398a87b39cce40e9875b5c0984eecdf963</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25558073$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Trubiano, J A</creatorcontrib><creatorcontrib>Crowe, A</creatorcontrib><creatorcontrib>Worth, L J</creatorcontrib><creatorcontrib>Thursky, K A</creatorcontrib><creatorcontrib>Slavin, M A</creatorcontrib><title>Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort</title><title>Journal of antimicrobial chemotherapy</title><addtitle>J Antimicrob Chemother</addtitle><description>The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD.
As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured.
The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%).
Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.</description><subject>Aged</subject><subject>Antibiotics</subject><subject>Antifungal Agents - adverse effects</subject><subject>Antifungal Agents - therapeutic use</subject><subject>Cohort Studies</subject><subject>Cytochrome P-450 CYP2C19 - genetics</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Fungal infections</subject><subject>Genomics</subject><subject>Genotyping Techniques</subject><subject>Hematologic Neoplasms - complications</subject><subject>Humans</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mycoses - drug therapy</subject><subject>Patients</subject><subject>Pharmacogenetics - methods</subject><subject>Pharmacology</subject><subject>Pilot Projects</subject><subject>Treatment Outcome</subject><subject>Voriconazole - adverse effects</subject><subject>Voriconazole - therapeutic use</subject><issn>0305-7453</issn><issn>1460-2091</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1Lw0AURQdRbK1u_AEy4E6IfcnMJBl3EvyCgl3owlWYTF6a1CRTJ5NC-utNaXV14XG4l3cIufbh3gfJ5mul5_l3LwJ5QqY-D8ELQPqnZAoMhBdxwSbkouvWABCKMD4nk0AIEUPEpmS37J2r2hVNvpZB4ku6wta4YbM_OUNdidRh5x5o76q6cgM1Bd2UyjZKmz3aVJriVtW9cpVpadVSRbfGVtq0amdq9JxF5TCnpcJGOVOb1UC1KY11l-SsUHWHV8eckc_np4_k1Vu8v7wljwtPB7HvvIxxGUSK86wAnnEslI7CvNAYBBGDjMlYxdEYWiMHlHEkMqFBxhxR54UM2YzcHno31vz04zPp2vS2HSdTPww5YwARH6m7A6Wt6TqLRbqxVaPskPqQ7jWno-b0oHmEb46VfdZg_o_-eWW_v_V7lA</recordid><startdate>201504</startdate><enddate>201504</enddate><creator>Trubiano, J A</creator><creator>Crowe, A</creator><creator>Worth, L J</creator><creator>Thursky, K A</creator><creator>Slavin, M A</creator><general>Oxford Publishing Limited (England)</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>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope></search><sort><creationdate>201504</creationdate><title>Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort</title><author>Trubiano, J A ; Crowe, A ; Worth, L J ; Thursky, K A ; Slavin, M A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c281t-b34927a44bf04b4efac76dfce22730b398a87b39cce40e9875b5c0984eecdf963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>Antibiotics</topic><topic>Antifungal Agents - adverse effects</topic><topic>Antifungal Agents - therapeutic use</topic><topic>Cohort Studies</topic><topic>Cytochrome P-450 CYP2C19 - genetics</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Fungal infections</topic><topic>Genomics</topic><topic>Genotyping Techniques</topic><topic>Hematologic Neoplasms - complications</topic><topic>Humans</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mycoses - drug therapy</topic><topic>Patients</topic><topic>Pharmacogenetics - methods</topic><topic>Pharmacology</topic><topic>Pilot Projects</topic><topic>Treatment Outcome</topic><topic>Voriconazole - adverse effects</topic><topic>Voriconazole - therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Trubiano, J A</creatorcontrib><creatorcontrib>Crowe, A</creatorcontrib><creatorcontrib>Worth, L J</creatorcontrib><creatorcontrib>Thursky, K A</creatorcontrib><creatorcontrib>Slavin, M A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Journal of antimicrobial chemotherapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Trubiano, J A</au><au>Crowe, A</au><au>Worth, L J</au><au>Thursky, K A</au><au>Slavin, M A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort</atitle><jtitle>Journal of antimicrobial chemotherapy</jtitle><addtitle>J Antimicrob Chemother</addtitle><date>2015-04</date><risdate>2015</risdate><volume>70</volume><issue>4</issue><spage>1161</spage><epage>1165</epage><pages>1161-1165</pages><issn>0305-7453</issn><eissn>1460-2091</eissn><abstract>The clinical utility of pharmacogenomic testing in haematology patients with invasive fungal disease (IFD) receiving azole therapy has not been defined. We report our experience with CYP2C19 testing in haematological patients requiring voriconazole therapy for IFD.
As a single-centre pilot study, 19 consecutive patients with a haematological malignancy undergoing active chemotherapy with a possible, probable or proven IFD requiring voriconazole therapy underwent CYP2C19 testing from 2013 to 2014. Baseline patient demographics, concurrent medications, voriconazole levels and IFD history were captured.
The median voriconazole levels for intermediate metabolizer (IM) (CYP2C19*2 or 3/*1 or 17), extensive metabolizer (EM) (CYP2C19*1/*1) and heterozygote ultrarapid metabolizer (HUM)/ultrarapid metabolizer (UM) (UM, CYP2C19*17/*17; HUM, CYP2C19*1/*17) patients were 5.23, 3.3 and 1.25 mg/L, respectively. Time to therapeutic voriconazole levels was longest in the IM group, whilst voriconazole levels <1 mg/L were only seen in UM, HUM and EM phenotypes. The highest rates of clinical toxicity were seen in the IM group (3/5, 60%).
Voriconazole exposure and toxicity was highest for IM and lowest for HUM/UM phenotypes. Time to therapeutic voriconazole level was longest in IM, whilst refractory subtherapeutic levels requiring CYP2C19 inhibition were only seen in the EM, HUM and UM phenotypes. CYP2C19 genotyping may predict those likely to have supratherapeutic or subtherapeutic levels and/or toxicity. Prospective evaluation of clinical pathways incorporating genotyping and voriconazole dose-titrating algorithms is required.</abstract><cop>England</cop><pub>Oxford Publishing Limited (England)</pub><pmid>25558073</pmid><doi>10.1093/jac/dku529</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Oxford University Press Journals All Titles (1996-Current); EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Aged Antibiotics Antifungal Agents - adverse effects Antifungal Agents - therapeutic use Cohort Studies Cytochrome P-450 CYP2C19 - genetics Drug therapy Female Fungal infections Genomics Genotyping Techniques Hematologic Neoplasms - complications Humans Male Middle Aged Mycoses - drug therapy Patients Pharmacogenetics - methods Pharmacology Pilot Projects Treatment Outcome Voriconazole - adverse effects Voriconazole - therapeutic use |
| title | Putting CYP2C19 genotyping to the test: utility of pharmacogenomic evaluation in a voriconazole-treated haematology cohort |
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