{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:42:02Z","timestamp":1788309722843,"version":"build-2803163510"},"reference-count":41,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,6,14]],"date-time":"2025-06-14T00:00:00Z","timestamp":1749859200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["288164"],"award-info":[{"award-number":["288164"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Rituximab (RTX) is used off\u2010label for relapsing\u2013remitting multiple sclerosis, although dosing regimens vary. Observational data suggest the standard 6\u2010month interval may be extended and individualized. We aimed to develop a pharmacokinetic\u2013pharmacodynamic (PKPD) model to describe patient\u2010specific RTX concentrations and CD19+\u2009lymphocyte counts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Thirteen treatment\u2010na\u00efve patients initiated RTX treatment with 1000\u2009mg intravenously. Blood samples were collected at 6 time points during the following 6 months. RTX concentrations and CD19+\u2009lymphocyte counts were used to compare different PKPD using the nonlinear mixed\u2010effects software Monolix.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Initial pharmacokinetics of RTX could be described by a 1\u2010compartment model with nonlinear target\u2010mediated elimination of rituximab. Introduction of CD19+\u2009lymphocyte counts as a pharmacodynamic marker resulted in comparable performance of a 1\u2010compartment and a 2\u2010compartment model and can provide descriptions of RTX concentrations and CD19+\u2009lymphocyte counts in individual patients. In both models, nonspecific clearance (CL) contributes approximately 10 times more to the overall elimination than target\u2010mediated clearance (k<jats:sub>deg,1<\/jats:sub>; CL [1\/day]\u2009=\u00a00.075\u2009\u00b1\u00a00.035 [median 0.061], k<jats:sub>deg,1<\/jats:sub> [mm<jats:sup>\u22123<\/jats:sup>\/day]\u2009=\u00a00.125\u2009\u00b1\u00a00.311 [median 0.007] and CL [1\/day]\u2009=\u00a00.036\u2009\u00b1\u00a00.027 [median 0.026], k<jats:sub>deg,1<\/jats:sub> [mm<jats:sup>\u22123<\/jats:sup>\/day]\u2009=\u00a00.004\u2009\u00b1\u00a00.002 [median 0.003]).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The PKPD models were able to describe the data both in patients exhibiting enduring CD19+\u2009lymphocyte depletion and in patients exhibiting signs of early CD19+\u2009lymphocyte repopulation. Additional data are required to validate and advance models for prediction of repopulation dynamics and, eventually, individualized RTX dosing.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bcp.70136","type":"journal-article","created":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T08:17:48Z","timestamp":1750148268000},"page":"2988-2997","source":"Crossref","is-referenced-by-count":1,"title":["Pharmacokinetic\u2013pharmacodynamic modelling in a clinical pilot study of rituximab in multiple sclerosis: Towards personalized dosing interval"],"prefix":"10.1002","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7475-1147","authenticated-orcid":false,"given":"Trond Tr\u00e6tteberg","family":"Serkland","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Pharmacology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silje","family":"Skrede","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Pharmacology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Science University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik Ingmar","family":"Hallin","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Pharmacology Haukeland University Hospital  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kjell\u2010Morten","family":"Myhr","sequence":"additional","affiliation":[{"name":"Neuro\u2010SysMed, Department of Neurology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d8ivind","family":"Torkildsen","sequence":"additional","affiliation":[{"name":"Neuro\u2010SysMed, Department of Neurology Haukeland University Hospital  Bergen Norway"},{"name":"Department of Clinical Medicine University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"R\u00f6blitz","sequence":"additional","affiliation":[{"name":"Computational Biology Unit, Department of Informatics University of Bergen  Bergen Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.26858"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582\u2010023\u201000775\u20105"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410430409"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/5532"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aab4176"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1179\/016164106X98099"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458517713668"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1080\/14712598.2019.1568407"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263\u2010021\u201000843\u20108"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003331"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415\u2010020\u201010362\u2010z"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181e24373"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706383"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2017.4011"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/ene.13936"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/2055217320973049"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2023.104729"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0000000000000681"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200056"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/13524585211065711"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a029058"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23115877"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14658"},{"key":"e_1_2_11_25_1","unstructured":"Clinical trials.Rituximab and ocrelizumab in serum with multiple sclerosis (ROS\u2010MS). 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