{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T15:45:05Z","timestamp":1786981505740,"version":"build-2736575974"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM124046"],"award-info":[{"award-number":["R01GM124046"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["3899\/H2020\/2018\/2"],"award-info":[{"award-number":["3899\/H2020\/2018\/2"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pharm Res"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To investigate how obesity affects the pharmacokinetics of biologics in a rat model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>Male Long-Evans rats were fed a high-fat diet from the age of 3\u00a0weeks and development of obesity was monitored by measuring body size and composition (fat and lean mass). The animals received nivolumab (1 and 8\u00a0mg\/kg) or recombinant human erythropoietin (rHuEPO, 1000\u00a0IU\/kg) by intravenous or subcutaneous injection. Serum samples were collected and analyzed using an enzyme-linked immunosorbent assay (ELISA). Endogenous rat IgG was also measured in the nivolumab study. A standard noncompartmental analysis was performed to calculate pharmacokinetic parameters.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>When dosed at mg\/kg of total body weight approach, no significant differences in pharmacokinetics of nivolumab and rHuEPO between lean and obese cohorts were observed despite significant differences in the body composition. Subcutaneous bioavailability of nivolumab was inversely dependent on the dose level.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Pharmacokinetic parameters of two biologics tested in this work were not affected by obesity, and mg\/kg dosing approach was necessary to achieve equivalent exposure\u00a0in serum. The results were different from our previous findings of significant effect of obesity on pharmacokinetics of human IgG in rats. Additional studies with other biologics are urgently needed in preclinical and clinical settings.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-025-03819-1","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T15:53:31Z","timestamp":1737647611000},"page":"271-280","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Pharmacokinetics of Nivolumab and Erythropoietin in a Rat Model of Diet-Induced Obesity"],"prefix":"10.1007","volume":"42","author":[{"given":"Yi-Hua","family":"Sheng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celine","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yae Eun","family":"Chong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Yohn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Siemi\u0105tkowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katarzyna","family":"Kosicka-Noworzy\u0144","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amrit","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karan","family":"Sapra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Brunetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3863-4757","authenticated-orcid":false,"given":"Leonid","family":"Kagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"3819_CR1","unstructured":"Stierman B, Afful J, Carroll MD, Chen T-C, Davy O, Fink S, et al. National health and nutrition examination survey 2017\u2013March 2020 prepandemic data files development of files and prevalence estimates for selected health outcomes. 2021."},{"issue":"Suppl 1","key":"3819_CR2","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1111\/dom.14290","volume":"23","author":"S Sarma","year":"2021","unstructured":"Sarma S, Sockalingam S, Dash S. Obesity as a multisystem disease: trends in obesity rates and obesity-related complications. Diabetes Obes Metab. 2021;23(Suppl 1):3\u201316.","journal-title":"Diabetes Obes Metab"},{"issue":"11","key":"3819_CR3","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1038\/aps.2012.51","volume":"33","author":"L Zhao","year":"2012","unstructured":"Zhao L, Ren TH, Wang DD. Clinical pharmacology considerations in biologics development. Acta Pharmacol Sin. 2012;33(11):1339\u201347.","journal-title":"Acta Pharmacol Sin"},{"issue":"9","key":"3819_CR4","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1111\/j.1468-3083.2011.04065.x","volume":"25","author":"L Puig","year":"2011","unstructured":"Puig L. Obesity and psoriasis: body weight and body mass index influence the response to biological treatment. J Eur Acad Dermatol Venereol. 2011;25(9):1007\u201311.","journal-title":"J Eur Acad Dermatol Venereol"},{"issue":"9","key":"3819_CR5","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1177\/0091270009337512","volume":"49","author":"DD Wang","year":"2009","unstructured":"Wang DD, Zhang S, Zhao H, Men AY, Parivar K. Fixed dosing versus body size-based dosing of monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012\u201324.","journal-title":"J Clin Pharmacol"},{"issue":"4","key":"3819_CR6","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/cpt.875","volume":"103","author":"K Ogungbenro","year":"2018","unstructured":"Ogungbenro K, Patel A, Duncombe R, Nuttall R, Clark J, Lorigan P. Dose rationalization of pembrolizumab and nivolumab using pharmacokinetic modeling and simulation and cost analysis. Clin Pharmacol Ther. 2018;103(4):582\u201390.","journal-title":"Clin Pharmacol Ther"},{"issue":"3","key":"3819_CR7","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1002\/cpt.1645","volume":"107","author":"AM Novakovic","year":"2020","unstructured":"Novakovic AM, Wilkins JJ, Dai H, Wade JR, Neuteboom B, Brar S, et al. Changing body weight\u2013based dosing to a flat dose for avelumab in metastatic merkel cell and advanced urothelial carcinoma. Clin Pharmacol Ther. 2020;107(3):588\u201396.","journal-title":"Clin Pharmacol Ther"},{"issue":"12","key":"3819_CR8","doi-asserted-by":"publisher","first-page":"e552","DOI":"10.1016\/S1470-2045(22)00554-X","volume":"23","author":"R Malmberg","year":"2022","unstructured":"Malmberg R, Zietse M, Dumoulin DW, Hendrikx JJ, Aerts JG, van der Veldt AA, et al. Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab. Lancet Oncol. 2022;23(12):e552\u201361.","journal-title":"Lancet Oncol"},{"issue":"1","key":"3819_CR9","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1177\/0091270010388648","volume":"52","author":"S Zhang","year":"2012","unstructured":"Zhang S, Shi R, Li C, Parivar K, Wang DD. Fixed dosing versus body size-based dosing of therapeutic peptides and proteins in adults. J Clin Pharmacol. 2012;52(1):18\u201328.","journal-title":"J Clin Pharmacol"},{"issue":"5","key":"3819_CR10","doi-asserted-by":"publisher","first-page":"1223","DOI":"10.1007\/s11095-023-03496-y","volume":"40","author":"X Gao","year":"2023","unstructured":"Gao X, Sheng YH, Yu S, Li J, Rosa R, Girgis S, et al. Mechanisms of obesity-induced changes in pharmacokinetics of IgG in rats. Pharm Res. 2023;40(5):1223\u201338.","journal-title":"Pharm Res"},{"key":"3819_CR11","doi-asserted-by":"crossref","unstructured":"Brunetti L, Chapy H, Nahass RG, Moore R, Wassef A, Adler D, et al. Relationship between body composition and serum immunoglobulin concentrations after administration of intravenous immune globulin-preclinical and clinical evidence. Pharmaceutics. 2023;15(2).","DOI":"10.3390\/pharmaceutics15020510"},{"issue":"16","key":"3819_CR12","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","volume":"381","author":"J Larkin","year":"2019","unstructured":"Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535\u201346.","journal-title":"N Engl J Med"},{"issue":"6","key":"3819_CR13","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1056\/NEJMoa2215530","volume":"389","author":"M Provencio","year":"2023","unstructured":"Provencio M, Nadal E, Gonz\u00e1lez-Larriba JL, Mart\u00ednez-Mart\u00ed A, Bernab\u00e9 R, Bosch-Barrera J, et al. Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2023;389(6):504\u201313.","journal-title":"N Engl J Med"},{"key":"3819_CR14","unstructured":"OPDIVO (nivolumab) injection label. Available from: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2022\/125554s112lbl.pdf. Accessed\u00a01 Oct 2024."},{"key":"3819_CR15","doi-asserted-by":"crossref","unstructured":"Collet L, Delrieu L, Bouhamama A, Crochet H, Swalduz A, Nerot A, et al. Association between body mass index and survival outcome in metastatic cancer patients treated by immunotherapy: analysis of a French retrospective cohort. Cancers (Basel). 2021;13(9).","DOI":"10.3390\/cancers13092200"},{"key":"3819_CR16","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.ejca.2019.11.003","volume":"124","author":"L Hirsch","year":"2020","unstructured":"Hirsch L, Bellesoeur A, Boudou-Rouquette P, Arrondeau J, Thomas-Schoemann A, Kirchgesner J, et al. The impact of body composition parameters on severe toxicity of nivolumab. Eur J Cancer. 2020;124:170\u20137.","journal-title":"Eur J Cancer"},{"key":"3819_CR17","doi-asserted-by":"crossref","unstructured":"McManus HD, Zhang D, Schwartz FR, Wu Y, Infield J, Ho E, et al. Relationship between pretreatment body composition and clinical outcomes in patients with metastatic renal cell carcinoma receiving first-line ipilimumab plus nivolumab. Clin Genitourin Cancer. 2023.","DOI":"10.1016\/j.clgc.2023.05.006"},{"issue":"3","key":"3819_CR18","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1159\/000455387","volume":"45","author":"K Kalantar-Zadeh","year":"2017","unstructured":"Kalantar-Zadeh K. History of erythropoiesis-stimulating agents, the development of biosimilars, and the future of anemia treatment in nephrology. Am J Nephrol. 2017;45(3):235\u201347.","journal-title":"Am J Nephrol"},{"key":"3819_CR19","unstructured":"PROCRIT (epoetin alfa) injection label. Available from: https:\/\/www.janssenlabels.com\/package-insert\/product-monograph\/prescribing-information\/PROCRIT-pi.pdf. Accessed\u00a01 Oct 2024."},{"issue":"10","key":"3819_CR20","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1634\/theoncologist.2017-0167","volume":"22","author":"J Hendrikx","year":"2017","unstructured":"Hendrikx J, Haanen J, Voest EE, Schellens JHM, Huitema ADR, Beijnen JH. Fixed dosing of monoclonal antibodies in oncology. Oncologist. 2017;22(10):1212\u201321.","journal-title":"Oncologist"},{"issue":"6","key":"3819_CR21","doi-asserted-by":"publisher","first-page":"2106","DOI":"10.1002\/cam4.2888","volume":"9","author":"E Hall","year":"2020","unstructured":"Hall E, Zhang J, Kim EJ, Hwang G, Chu G, Bhatia S, et al. Economics of alternative dosing strategies for pembrolizumab and nivolumab at a single academic cancer center. Cancer Med. 2020;9(6):2106\u201312.","journal-title":"Cancer Med"},{"issue":"12","key":"3819_CR22","doi-asserted-by":"publisher","first-page":"e552","DOI":"10.1016\/S1470-2045(22)00554-X","volume":"23","author":"R Malmberg","year":"2022","unstructured":"Malmberg R, Zietse M, Dumoulin DW, Hendrikx J, Aerts J, van der Veldt AAM, et al. Alternative dosing strategies for immune checkpoint inhibitors to improve cost-effectiveness: a special focus on nivolumab and pembrolizumab. Lancet Oncol. 2022;23(12):e552\u201361.","journal-title":"Lancet Oncol"},{"issue":"2","key":"3819_CR23","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s40259-022-00522-0","volume":"36","author":"M Bassi","year":"2022","unstructured":"Bassi M, Singh S. Impact of obesity on response to biologic therapies in patients with inflammatory bowel diseases. BioDrugs. 2022;36(2):197\u2013203.","journal-title":"BioDrugs"},{"issue":"3","key":"3819_CR24","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1111\/j.1365-2036.2011.04946.x","volume":"35","author":"E Bultman","year":"2012","unstructured":"Bultman E, de Haar C, van Liere-Baron A, Verhoog H, West RL, Kuipers EJ, et al. Predictors of dose escalation of adalimumab in a prospective cohort of Crohn\u2019s disease patients. Aliment Pharmacol Ther. 2012;35(3):335\u201341.","journal-title":"Aliment Pharmacol Ther"},{"key":"3819_CR25","doi-asserted-by":"crossref","unstructured":"Klaasen R, Wijbrandts CA, Gerlag DM, Tak PP. Body mass index and clinical response to infliximab in rheumatoid arthritis. Arthritis Rheum. 2011;63(2):359\u201364.","DOI":"10.1002\/art.30136"},{"issue":"6","key":"3819_CR26","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1093\/ibd\/izaa214","volume":"27","author":"ECL Wong","year":"2021","unstructured":"Wong ECL, Marshall JK, Reinisch W, Narula N. Body mass index does not impact clinical efficacy of ustekinumab in Crohn\u2019s disease: a post hoc analysis of the IM-UNITI trial. Inflamm Bowel Dis. 2021;27(6):848\u201354.","journal-title":"Inflamm Bowel Dis"},{"issue":"1","key":"3819_CR27","doi-asserted-by":"publisher","first-page":"103","DOI":"10.5455\/javar.2020.g399","volume":"7","author":"JB Suleiman","year":"2020","unstructured":"Suleiman JB, Mohamed M, Bakar ABA. A systematic review on different models of inducing obesity in animals: advantages and limitations. J Adv Vet Anim Res. 2020;7(1):103\u201314.","journal-title":"J Adv Vet Anim Res"},{"issue":"7","key":"3819_CR28","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.1016\/j.xphs.2018.03.006","volume":"107","author":"H Chapy","year":"2018","unstructured":"Chapy H, Kagan L. Evaluation of the effects of animal growth and previous exposure on the pharmacokinetics of rituximab in rats. J Pharm Sci. 2018;107(7):1987\u201394.","journal-title":"J Pharm Sci"},{"issue":"2","key":"3819_CR29","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1007\/s11095-011-0578-3","volume":"29","author":"L Kagan","year":"2012","unstructured":"Kagan L, Turner MR, Balu-Iyer SV, Mager DE. Subcutaneous absorption of monoclonal antibodies: role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharm Res. 2012;29(2):490\u20139.","journal-title":"Pharm Res"},{"issue":"12","key":"3819_CR30","doi-asserted-by":"publisher","first-page":"3265","DOI":"10.1007\/s11095-014-1416-1","volume":"31","author":"L Kagan","year":"2014","unstructured":"Kagan L, Zhao J, Mager DE. Interspecies pharmacokinetic modeling of subcutaneous absorption of rituximab in mice and rats. Pharm Res. 2014;31(12):3265\u201373.","journal-title":"Pharm Res"},{"key":"3819_CR31","doi-asserted-by":"crossref","unstructured":"Bajaj G, Wang X, Agrawal S, Gupta M, Roy A, Feng Y. Model\u2010based population pharmacokinetic analysis of nivolumab in patients with solid tumors. CPT Pharmacomet Syst Pharmacol. 2017;6(1):58\u201366.","DOI":"10.1002\/psp4.12143"},{"issue":"3","key":"3819_CR32","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1093\/ndt\/gfl716","volume":"22","author":"J Rossert","year":"2007","unstructured":"Rossert J, Gassmann-Mayer C, Frei D, McClellan W. Prevalence and predictors of epoetin hyporesponsiveness in chronic kidney disease patients. Nephrol Dial Transplant. 2007;22(3):794\u2013800.","journal-title":"Nephrol Dial Transplant"},{"issue":"2","key":"3819_CR33","doi-asserted-by":"publisher","first-page":"148","DOI":"10.23876\/j.krcp.2018.37.2.148","volume":"37","author":"GM El-Kannishy","year":"2018","unstructured":"El-Kannishy GM, Megahed AF, Tawfik MM, El-Said G, Zakaria RT, Mohamed NA, et al. Obesity may be erythropoietin dose-saving in hemodialysis patients. Kidney Res Clin Pract. 2018;37(2):148\u201356.","journal-title":"Kidney Res Clin Pract"},{"issue":"12","key":"3819_CR34","doi-asserted-by":"publisher","first-page":"3027","DOI":"10.1002\/jps.20200","volume":"93","author":"K Jolling","year":"2004","unstructured":"Jolling K, Ruixo JJ, Hemeryck A, Piotrovskij V, Greway T. Population pharmacokinetic analysis of pegylated human erythropoietin in rats. J Pharm Sci. 2004;93(12):3027\u201338.","journal-title":"J Pharm Sci"}],"container-title":["Pharmaceutical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03819-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11095-025-03819-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11095-025-03819-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T03:58:09Z","timestamp":1741147089000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11095-025-03819-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":34,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["3819"],"URL":"https:\/\/doi.org\/10.1007\/s11095-025-03819-1","relation":{},"ISSN":["0724-8741","1573-904X"],"issn-type":[{"value":"0724-8741","type":"print"},{"value":"1573-904X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]},"assertion":[{"value":"12 November 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 January 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"None.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}}]}}