{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T18:57:02Z","timestamp":1781204222586,"version":"3.54.1"},"reference-count":46,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 DK026743"],"award-info":[{"award-number":["P30 DK026743"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The objective of this study was to determine the potential usefulness of an animal model to predict the appropriate dose of newly developed drugs for treating relapsing remitting multiple sclerosis (RRMS). Conversion of the lowest effective dose (LEffD) for mice and rats in the experimental autoimmune encephalomyelitis (EAE) model was used to predict the human effective dose utilizing the body surface area correction factor found in the 2005 US Food and Drug Administration (FDA) Guidance for Industry in selecting safe starting doses for clinical trials. Predictions were also tested by comparison with doses estimated by scaling up the LEffD in the model by the human to animal clearance ratio. Although initial proof\u2010of\u2010concept studies of oral fingolimod tested the efficacy and safety of 1.25 and 5\u00a0mg in treating RRMS, the EAE animal model predicted the approved dose of this drug, 0.5\u00a0mg daily. This approach would have also provided useful predictions of the approved human oral doses for cladribine, dimethyl fumarate, ozanimod, ponesimod, siponimod, and teriflunomide, drugs developed with more than one supposed mechanism of action. The procedure was not useful for i.v. dosed drugs, including monoclonal antibodies. We maintain that drug development scientists should always examine a simple allometric method to predict the therapeutic effective dose in humans. Then, following clinical studies, we believe that the animal model might be expected to yield useful predictions of other drugs developed to treat the same condition. The methodology may not always be predictive, but the approach is so simple it should be investigated.<\/jats:p>","DOI":"10.1111\/cts.13458","type":"journal-article","created":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T13:15:26Z","timestamp":1669295726000},"page":"467-477","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Using an animal model to predict the effective human dose for oral multiple sclerosis drugs"],"prefix":"10.1111","volume":"16","author":[{"given":"Wei","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacy Peking University Third Hospital  Beijing China"},{"name":"Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiheng","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Peking University Third Hospital  Beijing China"},{"name":"Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Peking University Third Hospital  Beijing China"},{"name":"School of Basic Medical Sciences and Clinical Pharmacy China Pharmaceutical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle L.","family":"Waubant","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences and San Francisco Multiple Sclerosis Center University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suodi","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Peking University Third Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-2371","authenticated-orcid":false,"given":"Leslie Z.","family":"Benet","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Peking University Third Hospital  Beijing China"},{"name":"Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine University of California San Francisco  San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa052643"},{"key":"e_1_2_11_3_1","unstructured":"Fingolimod (GILENYA) Drug Label Washington (USA).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2010\/022527s000lbl.pdf. Accessed March 28 2022."},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2011.01302.x"},{"key":"e_1_2_11_5_1","unstructured":"Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers 2005 Rockville MD.https:\/\/www.fda.gov\/media\/72309\/download. Accessed March 28 2022."},{"key":"e_1_2_11_6_1","unstructured":"Ofatumumab Pharmacology Review(s) Washington (USA).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2009\/125326s000_PharmR.pdf. Accessed March 28 2022."},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2013.05.016"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1185\/03007995.2011.583229"},{"key":"e_1_2_11_9_1","unstructured":"Dalfampridine (AMPYRA) Drug Label Washington (USA).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2010\/022250s000lbl.pdf. Accessed March 28 2022."},{"key":"e_1_2_11_10_1","first-page":"439","article-title":"FTY720, sphingosine 1\u2010phosphate receptor modulator, ameliorates experimental autoimmune encephalomyelitis by inhibition of T cell infiltration","volume":"2","author":"Kataoka H","year":"2005","journal-title":"Cell Mol Immunol"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2004.04.015"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.TP.0000084822.01372.AC"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.105.009001"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-009-0075-3"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.251"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1603907113"},{"key":"e_1_2_11_17_1","unstructured":"Dimethyl Fumarate (TECFIDERA) Washington (USA).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2013\/204063lbl.pdf. Accessed March 28 2022."},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2013.08.009"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02061.x"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13476"},{"key":"e_1_2_11_21_1","unstructured":"Ponesimod (PONVORY) Non\u2010clinical Reviews Washington (USA).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2021\/213498s000lbl.pdf. Accessed March 28 2022."},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.7.3842"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1309.055"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10072-009-0142-7"},{"key":"e_1_2_11_25_1","unstructured":"Mitoxantrone Pharmacology Review(s) Washington (USA).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2000\/21120.pdf_Novantrone_Pharmr_P1.pdf. Accessed March 28 2022."},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(87)90118-8"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-1229(85)90075-3"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awl083"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-52001-2.00008-X"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2015.05.018"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/356063a0"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2005.08.014"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.20913"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.22081"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001393"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e318234d421"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017103"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2016.06.026"},{"key":"e_1_2_11_39_1","unstructured":"Daclizumab (ZINBRYTA) Drug Label Washington (USA).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2016\/761029s000lbl.pdf. Accessed March 28 2022."},{"key":"e_1_2_11_40_1","unstructured":"FDA.FDA working with manufacturers to withdraw Zinbryta from the market in the United States. Drug Safety and Availability. March 14 2018.https:\/\/www.fda.gov\/drugs\/drug\u2010safety\u2010and\u2010availability\/fda\u2010working\u2010manufacturers\u2010withdraw\u2010zinbryta\u2010market\u2010united\u2010states. Accessed March 28 2022"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.6.3301"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.9606"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.473"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1295"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00292881"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.22011"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-014-1416-1"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13458","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.13458","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.13458","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T22:14:39Z","timestamp":1692656079000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.13458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,23]]},"references-count":46,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2023,3]]}},"alternative-id":["10.1111\/cts.13458"],"URL":"https:\/\/doi.org\/10.1111\/cts.13458","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,23]]},"assertion":[{"value":"2022-07-31","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-23","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}