{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,13]],"date-time":"2026-03-13T01:58:19Z","timestamp":1773367099121,"version":"3.50.1"},"reference-count":26,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T00:00:00Z","timestamp":1742169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:p>Pediatric patients with advanced\u2010stage newly diagnosed Hodgkin lymphoma (HL) were treated with brentuximab vedotin (BV) combined with adriamycin, vinblastine, and dacarbazine (A + AVD). Weight\u2010based BV dosing is employed in adult patients, while both body weight\u2010 and body surface area (BSA)\u2010based dosing are used in pediatric patients. Data from two pediatric studies were used for a population pharmacokinetics (PK) analysis. Study 1 was a phase I\/II dose\u2010escalation study in which patients with relapsed or refractory systemic anaplastic large\u2010cell lymphoma or HL received single\u2010agent weight\u2010based BV 1.4\u20131.8\u2009mg\/kg every 3\u2009weeks. Study 2 tested BSA\u2010based BV 48\u2009mg\/m<jats:sup>2<\/jats:sup> every 2\u2009weeks with AVD in patients with advanced\u2010stage, newly diagnosed HL. Sources of PK variability were quantified using nonlinear mixed\u2010effects modeling. The relationships between antibody\u2010drug conjugate (ADC) or payload monomethyl auristatin E (MMAE) exposures and progression\u2010free survival (PFS) or incidence of adverse events were analyzed by Cox proportional hazards and logistic regression, respectively. Population PK models of ADC and MMAE were developed using data from 95 patients. BSA was identified as a significant covariate for the clearance of ADC and MMAE. BSA\u2010based BV dosing resulted in similar systemic exposures of ADC and MMAE in pediatric patients across age groups (&lt;\u200912, 12\u201316, and &gt;\u200916\u2009years). A significant increase (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.05) in the incidence of febrile neutropenia was related to increasing exposure of MMAE. No apparent relationship was identified between ADC or MMAE exposures and PFS. The analyses support BSA\u2010based BV dosing in combination with AVD in pediatric patients.<\/jats:p>","DOI":"10.1002\/cpt.3629","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T12:09:07Z","timestamp":1742213347000},"page":"1803-1810","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Optimizing Brentuximab Vedotin Dosing in Pediatric Patients with Advanced Hodgkin Lymphoma: A Population Pharmacokinetic and Exposure\u2010Response Analysis"],"prefix":"10.1002","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0319-1327","authenticated-orcid":false,"given":"Xiaofei","family":"Zhou","sequence":"first","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Lexington Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8908-0136","authenticated-orcid":false,"given":"Diane R.","family":"Mould","sequence":"additional","affiliation":[{"name":"Projections Research, Inc.  Phoenixville Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lia","family":"Gore","sequence":"additional","affiliation":[{"name":"Children's Hospital Colorado Center for Cancer and Blood Disorders and University of Colorado School of Medicine  Aurora Colorado USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Bai","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Lexington Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5500-5218","authenticated-orcid":false,"given":"Neeraj","family":"Gupta","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Lexington Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"key":"e_1_2_11_1_1","unstructured":"ADCETRIS\u00ae (brentuximab vedotin) summary of product characteristics<https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/adcetris\u2010epar\u2010product\u2010information_en.pdf> (2022)."},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004710"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(21)00102-2"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.12.002"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(18)30153-4"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1682"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.37_2879"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1295"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/cts.12527"},{"key":"e_1_2_11_10_1","unstructured":"U.S. Food and Drug Administration.Project optimus: reforming the dose optimization and dose 519 selection paradigm in oncology<https:\/\/www.fda.gov\/about520fda\/oncology\u2010center\u2010excellence\/project\u2010optimus> Accessed December 18 2023."},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2109826"},{"key":"e_1_2_11_12_1","unstructured":"Friends of Cancer Research.Optimizing dosing in oncology drug development(2021). 522 <https:\/\/friendsofcancerresearch.org\/wp523content\/uploads\/Optimizing_Dosing_in_Oncology_Drug_Development.pdf>. Accessed December 20 2023."},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00371"},{"key":"e_1_2_11_14_1","article-title":"Moving the needle for oncology dose optimization: a call for action","volume":"17","author":"Venkatakrishnan K.","year":"2024","journal-title":"CPT Pharmacometrics Syst. Pharmacol."},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3298"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.116"},{"key":"e_1_2_11_17_1","unstructured":"ADCETRIS\u00ae (brentuximab vedotin) prescribing information<https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/125388s106lbl.pdf> (2011)."},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1530"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270010388648"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40272-020-00382-7"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2012.10.005"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.920"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.16128"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.656"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-012-0027-4"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12769"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.3629","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,25]],"date-time":"2025-05-25T17:17:29Z","timestamp":1748193449000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.3629"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,17]]},"references-count":26,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["10.1002\/cpt.3629"],"URL":"https:\/\/doi.org\/10.1002\/cpt.3629","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,17]]},"assertion":[{"value":"2024-10-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}