{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T04:20:59Z","timestamp":1764562859015,"version":"3.46.0"},"reference-count":19,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T00:00:00Z","timestamp":1740441600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["grant no. 21K16332"],"award-info":[{"award-number":["grant no. 21K16332"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008728","name":"Japan Research Foundation for Clinical Pharmacology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008728","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      The influence of\n                      <jats:italic>CYP2C19<\/jats:italic>\n                      polymorphisms on voriconazole plasma concentrations is recognized, but its extent, other contributing factors and risks for adverse reactions remain under\u2010explored.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This study focused on Japanese paediatric patients recruited between 2020 and 2022 treated with voriconazole. We specifically investigated the occurrence of cholestasis and thrombocytopenia as adverse reactions of voriconazole. Voriconazole plasma levels were modelled in a previous study using a population pharmacokinetics approach. Missing values were estimated with a Bayesian method in Phoenix NLME. We analysed\n                      <jats:italic>CYP2C19*2<\/jats:italic>\n                      ,\n                      <jats:italic>CYP2C19*3<\/jats:italic>\n                      and\n                      <jats:italic>CYP2C19*17<\/jats:italic>\n                      . Clinical and laboratory data were collected before and after voriconazole treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among the 60 patients (mean age: 6.5\u00a0years; 53.3% male), 38 had haematological malignancies, 18 inborn errors of immunity, 2 solid tumours and 2 other diseases. Adverse reactions occurred in 12 patients. The voriconazole plasma concentrations were significantly higher in those experiencing these adverse reactions (mean normalized concentrations: 0.66 in cases\n                      <jats:italic>vs<\/jats:italic>\n                      . \u22120.16 in controls,\n                      <jats:italic>P\u2009=<\/jats:italic>\n                      \u2009.025), with a trend towards higher concentrations in carriers of the\n                      <jats:italic>CYP2C19*2<\/jats:italic>\n                      or\n                      <jats:italic>*3<\/jats:italic>\n                      alleles (mean normalized concentrations: 0.98 in carrier cases\n                      <jats:italic>vs<\/jats:italic>\n                      . 0.016 in noncarrier cases,\n                      <jats:italic>P\u2009=<\/jats:italic>\n                      \u2009.14). A predictive model for voriconazole concentrations, incorporating carriership of\n                      <jats:italic>CYP2C19*2<\/jats:italic>\n                      or\n                      <jats:italic>*3<\/jats:italic>\n                      , C\u2010reactive protein levels, and platelet counts, showed a summed variance explained of 23.6% with the variance attributable to\n                      <jats:italic>CYP2C19*2<\/jats:italic>\n                      or\n                      <jats:italic>*3<\/jats:italic>\n                      carrier status alone was 2.6%. Including carrier status improved the area under the receiver operating characteristic curve for predicting adverse reactions to 0.70.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our findings underscore the role of the\n                      <jats:italic>CYP2C19<\/jats:italic>\n                      polymorphism in voriconazole\u2010induced thrombocytopenia and cholestasis.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70026","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T19:49:07Z","timestamp":1740599347000},"page":"2020-2027","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of factors influencing the relationship between voriconazole plasma concentrations and adverse effects in a paediatric population"],"prefix":"10.1002","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4852-2401","authenticated-orcid":false,"given":"Keiko","family":"Hikino","sequence":"first","affiliation":[{"name":"Laboratory for Pharmacogenomics RIKEN Center for Integrative Medical Sciences  Yokohama City Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kensuke","family":"Shoji","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medical Subspecialties National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4799-5562","authenticated-orcid":false,"given":"Jumpei","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koya","family":"Fukunaga","sequence":"additional","affiliation":[{"name":"Laboratory for Pharmacogenomics RIKEN Center for Integrative Medical Sciences  Yokohama City Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoxi","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory for Statistical and Translational Genetics RIKEN Center for Integrative Medical Sciences  Yokohama City Kanagawa Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiro","family":"Matsui","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Medical Subspecialties National Center for Child Health and Development  Tokyo Japan"},{"name":"Children's Cancer Center National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyuki","family":"Utano","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Takebayashi","sequence":"additional","affiliation":[{"name":"Children's Cancer Center National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Tomizawa","sequence":"additional","affiliation":[{"name":"Children's Cancer Center National Center for Child Health and Development  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motohiro","family":"Kato","sequence":"additional","affiliation":[{"name":"Children's Cancer Center National Center for Child Health and Development  Tokyo 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