{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:59:30Z","timestamp":1790827170017,"version":"4.1.0"},"reference-count":32,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2020,12,6]],"date-time":"2020-12-06T00:00:00Z","timestamp":1607212800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:p>Trastuzumab deruxtecan (DS\u20108201) is a human epidermal growth factor receptor 2 (HER2)\u2013targeting antibody\u2013drug conjugate with a novel enzyme\u2010cleavable linker, a topoisomerase I inhibitor payload, and a drug\u2010to\u2010antibody ratio of \u2248 8. We have characterized the population pharmacokinetics (PK) of trastuzumab deruxtecan and released drug (topoisomerase I inhibitor) in patients with HER2\u2010positive breast cancer or other solid tumor malignancies. This analysis includes pooled data from five clinical studies with 639 patients. Trastuzumab deruxtecan doses ranged from 0.8 to 8.0\u00a0mg\/kg every 3\u00a0weeks. Serum concentrations of trastuzumab deruxtecan and released drug were analyzed using a sequential two\u2010step approach, with the nonlinear mixed\u2010effects modeling methods. Covariate assessment was based upon stepwise forward\u2010addition and backward\u2010elimination process, followed by both univariate and multivariate analysis quantifying their impact on steady\u2010state exposure of trastuzumab deruxtecan and released drug. A two\u2010compartment model with linear elimination best described PK profiles of intact trastuzumab deruxtecan, while a one\u2010compartment model with time\u2010varying release\u2010rate constant and linear elimination described released\u2010drug PK profiles. Statistically significant covariates (country, tumor size, sex, formulation, age, body weight, albumin, total bilirubin, and aspartate aminotransferase) resulted in &lt;\u00a020% change in steady\u2010state area under the concentration\u2010time curve of trastuzumab deruxtecan and released drug, except for increased body weight (95th percentile, 86\u00a0kg) and decreased albumin (5th percentile, 31\u00a0g\/L). Analysis of patients stratified by country, race, renal function, and hepatic function found no clinically meaningful differences in steady\u2010state exposure of intact trastuzumab deruxtecan or released drug. Overall, results suggest that no dose adjustment based on tested covariates or in specific patient populations is warranted.<\/jats:p>","DOI":"10.1002\/cpt.2096","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T06:07:28Z","timestamp":1603951648000},"page":"1314-1325","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Population Pharmacokinetics of Trastuzumab Deruxtecan in Patients With HER2\u2010Positive Breast Cancer and Other Solid Tumors"],"prefix":"10.1111","volume":"109","author":[{"given":"Ophelia","family":"Yin","sequence":"first","affiliation":[{"name":"Quantitative Clinical Pharmacology and Translational Sciences Daiichi Sankyo, Inc Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Certara Strategic Consulting Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiko","family":"Endo","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Department Daiichi Sankyo Co, Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazutaka","family":"Yoshihara","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Department Daiichi Sankyo Co, Ltd Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tushar","family":"Garimella","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology and Translational Sciences Daiichi Sankyo, Inc Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malaz","family":"AbuTarif","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology and Translational Sciences Daiichi Sankyo, Inc Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russ","family":"Wada","sequence":"additional","affiliation":[{"name":"Certara Strategic Consulting Princeton New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"LaCreta","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology and Translational Sciences Daiichi Sankyo, Inc Basking Ridge New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,12,6]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1002\/prca.201300105"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/dju055"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3798106"},{"key":"e_1_2_10_4_1","unstructured":"NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. V4.2020 <https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/breast.pdf> (2020). Accessed June 4 2020."},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12282-016-0670-y"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy192"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30604-6"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2822"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1248\/cpb.c18-00744"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1914510"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30097-X"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","DOI":"10.1158\/1538-7445.SABCS19-P1-18-12","article-title":"A phase 1, multicenter, open\u2010label study to assess the effect of [fam\u2010] trastuzumab deruxtecan (T\u2010DXd; DS\u20108201a) on QTc and pharmacokinetics in subjects with HER2\u2010expressing metastatic and\/or unresectable breast cancer [abstract P1\u201318\u201012]","volume":"80","author":"Yamashita T.","year":"2020","journal-title":"Cancer Res."},{"key":"e_1_2_10_13_1","article-title":"Safety and pharmacokinetic results from a phase 1, multicenter, open\u2010label study of [fam\u2010] trastuzumab deruxtecan (T\u2010DXd; DS\u20108201a) in subjects with advanced HER2\u2010positive breast cancer [abstract C041]","volume":"18","author":"Chang D.\u2010Y.","year":"2019","journal-title":"Mol. Cancer Ther."},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz242.025"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-0449"},{"key":"e_1_2_10_16_1","unstructured":"US Food and Drug Administration.Guidance for industry: pharmacokinetics in patients with impaired renal function\u2014study design data analysis and impact on dosing and labeling<https:\/\/www.fda.gov\/media\/78573\/download> (2010). Accessed June 4 2020."},{"key":"e_1_2_10_17_1","unstructured":"ecancer.FDA approves new treatment option for patients with HER2\u2010positive breast cancer who have progressed on available therapies<https:\/\/ecancer.org\/en\/news\/17123\u2010fda\u2010approves\u2010new\u2010treatment\u2010option\u2010for\u2010patients\u2010with\u2010her2\u2010positive\u2010breast\u2010cancer\u2010who\u2010have\u2010progressed\u2010on\u2010available\u2010therapies> (2019). Accessed June 4 2020."},{"key":"e_1_2_10_18_1","unstructured":"BioSpace.ENHERTU approved in Japan for treatment of patients with HER2 positive unresectable or metastatic breast cancer<https:\/\/www.biospace.com\/article\/releases\/enhertu\u2010approved\u2010in\u2010japan\u2010for\u2010treatment\u2010of\u2010patients\u2010with\u2010her2\u2010positive\u2010unresectable\u2010or\u2010metastatic\u2010breast\u2010cancer\u2010\/> (2020). Accessed June 4 2020."},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.2165\/11535960-000000000-00000"},{"key":"e_1_2_10_20_1","first-page":"84","article-title":"The pharmacokinetics and pharmacodynamics of monoclonal antibodies\u2014mechanistic modeling applied to drug development","volume":"10","author":"Mould D.R.","year":"2007","journal-title":"Curr. Opin. Drug Discov. Devel."},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-014-2400-5"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13996"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12224"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","DOI":"10.1200\/JCO.2018.36.15_suppl.2501","article-title":"Trastuzumab deruxtecan (DS\u20108201a) in subjects with HER2\u2010expressing solid tumors: Long\u2010term results of a large phase 1 study with multiple expansion cohorts [abstract 2501]","volume":"36","author":"Iwata H.","year":"2018","journal-title":"J. Clin. 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