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Autoreactive memory B cells, which have a decreased activation threshold and the ability to survive in absence of antigen, are believed to contribute to chronicity in autoimmune diseases like SLE. Belimumab, the first approved biological treatment of active SLE and lupus nephritis, reduces B cells dependent on B\u2010lymphocyte stimulator protein (BLyS) for survival, whereas memory B cells are spared; several studies reported circulating memory B\u2010cell concentrations increase following BLyS neutralization. This analysis investigated the effect of dose, demographics, and disease status on memory B\u2010cell response after starting belimumab treatment. Population pharmacodynamic models were fitted to a pooled dataset from seven belimumab SLE trials. The optimal model was selected using maximum likelihood methods and was then refit to the data using Bayesian analysis and used to simulate memory B\u2010cell response by belimumab dose and covariate subgroups. At the belimumab approved doses (10\u00a0mg\/kg intravenously every 4\u2009weeks, 200\u2009mg subcutaneously every week), circulatory memory B cells increase in the first 4\u20138\u2009weeks after belimumab initiation, typically returning to baseline levels over 76\u2009weeks. The model analysis suggested belimumab stimulates memory B\u2010cell transition from lymphoid and\/or inflamed tissues into the circulation, rather than inhibiting trafficking in the reverse direction. Baseline BLyS and anti\u2013double\u2010stranded deoxyribonucleic acid antibody concentrations were statistically identifiable covariates of memory B\u2010cell response, although their impact on predicting size and response duration was small.<\/jats:p>","DOI":"10.1002\/psp4.12919","type":"journal-article","created":{"date-parts":[[2023,3,5]],"date-time":"2023-03-05T08:00:37Z","timestamp":1678003237000},"page":"462-473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Population model\u2010based analysis of the memory B\u2010cell response following belimumab therapy in the treatment of systemic lupus erythematosus"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1246-5705","authenticated-orcid":false,"given":"Richard","family":"Dimelow","sequence":"first","affiliation":[{"name":"GSK, Clinical Pharmacology Modelling and Simulation  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4560-6482","authenticated-orcid":false,"given":"William R.","family":"Gillespie","sequence":"additional","affiliation":[{"name":"Metrum Research Group  Tariffville Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1954-0141","authenticated-orcid":false,"given":"Andre","family":"van Maurik","sequence":"additional","affiliation":[{"name":"GSK, Clinical Pharmacology and Experimental Medicine  Stevenage UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,2,27]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI38010"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.190.11.1697"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2018-025687"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.62.2.168"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23678"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.21526"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.11299"},{"key":"e_1_2_12_10_1","unstructured":"GSK.US highlights of prescribing information 2021."},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.34400"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1136\/lupus-2021-000499"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/3-540-29714-6_12"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2007.079418"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2021-eular.248"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1101230"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01787"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.12.040194.001001"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.24699"},{"key":"e_1_2_12_20_1","unstructured":"clinicaltrials.gov.Phase 2 study of belimumab administered subcutaneously to subjects with systemic lupus erythematosus (SLE) 2013.NCT00732940."},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2020-217101"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40049"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2017-211631"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.30613"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.41900"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02458"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.104"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-017-0586-5"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpdd.889"},{"key":"e_1_2_12_30_1","unstructured":"GastonguayM.Full Covariate Models as an Alternative to Methods Relying on Statistical Significance for Inferences About Covariate Effects: A Review of Methodology and 42 Case Studies. 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