{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T14:50:05Z","timestamp":1785250205163,"version":"3.55.0"},"reference-count":18,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2019,10,3]],"date-time":"2019-10-03T00:00:00Z","timestamp":1570060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2019,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>This study determined individual optimal amrubicin doses for Japanese patients with lung cancer after platinum\u2010based treatment. We carried out population pharmacokinetic and pharmacodynamic modeling incorporating gene polymorphisms of metabolizing enzymes and transporters. Fifty patients with lung cancer, who were given 35\u201040\u00a0mg\/m<jats:sup>2<\/jats:sup> amrubicin on days 1\u20103 every 3\u20104\u00a0weeks, were enrolled. Mechanism\u2010based modeling described relationships between the pharmacokinetics of amrubicin and absolute neutrophil counts. A population pharmacokinetic and pharmacodynamic model was developed for amrubicin and amrubicinol (active metabolite), connected by a delay compartment. The final model incorporated body surface area as a covariate of amrubicin and amrubicinol clearance and distribution volume. <jats:italic><jats:styled-content style=\"fixed-case\">SLC<\/jats:styled-content>28A3<\/jats:italic> single nucleotide polymorphism (rs7853758) was also incorporated as a constant covariate of the delay compartment of amrubicinol. Performance status was considered a covariate of pharmacokinetic (amrubicinol clearance) and pharmacodynamic (mean maturation time) parameters. Twenty\u2010nine patients with grade 4 neutropenia showed higher amrubicinol area under the plasma concentration\u2010time curve from 0 to 72\u00a0hours (<jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content><jats:sub>0\u201072<\/jats:sub>, <jats:italic>P\u00a0<\/jats:italic>=<jats:italic>\u00a0<\/jats:italic>.01) and shorter overall survival periods than other patients did (<jats:italic>P\u00a0<\/jats:italic>=<jats:italic>\u00a0<\/jats:italic>.01). Using the final population pharmacokinetic and pharmacodynamic model, median optimal dose to prevent grade 4 neutropenia aggravation was estimated at 22 (range, 8\u221240) mg\/m<jats:sup>2<\/jats:sup> for these 29 patients. We clarified correlations between area under the plasma concentration\u2010time curve from 0 to 72\u00a0hours of amrubicinol and severity of neutropenia and survival of patients given amrubicin after platinum chemotherapy. This analysis revealed important amrubicin pharmacokinetic\u2010pharmacodynamic covariates and provided useful information to predict patients who would require prophylactic granulocyte colony stimulating factor.<\/jats:p>","DOI":"10.1111\/cas.14194","type":"journal-article","created":{"date-parts":[[2019,9,10]],"date-time":"2019-09-10T17:54:41Z","timestamp":1568138081000},"page":"3573-3583","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Individual optimal dose of amrubicin to prevent severe neutropenia in Japanese patients with lung cancer"],"prefix":"10.1111","volume":"110","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2739-6458","authenticated-orcid":false,"given":"Yoshinori","family":"Makino","sequence":"first","affiliation":[{"name":"Department of Pharmacy National Cancer Center Hospital Tokyo Japan"},{"name":"Division of Pharmacokinetics\/Pharmacodynamics Department of Pharmacology, Toxicology, and Therapeutics School of Pharmacy Showa University Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reiko","family":"Makihara\u2010Ando","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Division of Pharmacokinetics\/Pharmacodynamics Department of Pharmacology, Toxicology, and Therapeutics School of Pharmacy Showa University Tokyo Japan"},{"name":"Certara G.K. Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Pharmacokinetics\/Pharmacodynamics Department of Pharmacology, Toxicology, and Therapeutics School of Pharmacy Showa University Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Kanda","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9090-801X","authenticated-orcid":false,"given":"Hidehito","family":"Horinouchi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6981-0800","authenticated-orcid":false,"given":"Yutaka","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6137-073X","authenticated-orcid":false,"given":"Yuichiro","family":"Ohe","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noboru","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology National Cancer Center Hospital Tokyo Japan"},{"name":"Department of Experimental Therapeutics Exploratory Oncology Research and Clinical Trial Center National Cancer Center Tokyo 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