{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T13:04:03Z","timestamp":1784379843963,"version":"3.55.0"},"reference-count":16,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T00:00:00Z","timestamp":1782518400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T00:00:00Z","timestamp":1782518400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Multiple sclerosis (MS) is a significant cause of neurological disability in young adults. Siponimod, a potent sphingosine\u20101\u2010phosphate (S1P) receptor modulator, is used to treat MS by reducing T\u2010cell recirculation and central inflammation. The presented work includes clinical data describing the impact of the CYP3A4 inhibitor clarithromycin on siponimod metabolism and the results of updated physiologically based pharmacokinetic (PBPK) modeling. A clinical drug\u2013drug interaction (DDI) study assessed the effect of clarithromycin on siponimod pharmacokinetics in healthy participants with the CYP2C9\n                    <jats:italic>*1*3<\/jats:italic>\n                    genotype. Results revealed minimal differences in PK: a 2% increase in\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    , an 8% increase in AUC\n                    <jats:sub>last<\/jats:sub>\n                    and a 9% increase in AUC\n                    <jats:sub>inf<\/jats:sub>\n                    , confirming no clinically relevant drug\u2013drug interaction (DDI). The existing siponimod PBPK model was updated using these DDI study data, estimating a CYP3A4 fraction metabolized of 6.4% in the CYP2C9*1*1 genotype. Simulations using the updated PBPK model in the absence and presence of the restricted co\u2010medication (CYP2C9 and CYP3A perpetrators) were conducted. There was no clinically relevant DDI with moderate and strong CYP3A4 inhibitors across CYP2C9 genotypes with a predicted maximum net AUC increase of 1.33. Co\u2010administration of fluconazole, a moderate CYP3A4 and CYP2C9 inhibitor, was predicted to result in &lt;\u20092\u2010fold net AUC increase, except for the genotype CYP2C9*2*2, where a 2.2\u2010fold net AUC increase compared to the CYP2C9 wild type without fluconazole co\u2010treatment was observed. Siponimod\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    and AUC were comparable across CYP2C9 genotypes during dose titration in the absence or presence of fluconazole, suggesting no impact on the effectiveness of the dose titration regimen.\n                  <\/jats:p>","DOI":"10.1111\/cts.70657","type":"journal-article","created":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T02:42:32Z","timestamp":1782614552000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>PBPK<\/scp>\n                    Modeling and Clinical Data Reveal Reduced Impact of\n                    <scp>CYP3A4<\/scp>\n                    and\n                    <scp>CYP2C9<\/scp>\n                    Inhibitors on Elimination of Siponimod"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7121-4394","authenticated-orcid":false,"given":"Felix","family":"Huth","sequence":"first","affiliation":[{"name":"Novartis Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5923-5953","authenticated-orcid":false,"given":"Kasra","family":"Shakeri\u2010Nejad","sequence":"additional","affiliation":[{"name":"Novartis Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6763-4665","authenticated-orcid":false,"given":"Anne","family":"Gardin","sequence":"additional","affiliation":[{"name":"Novartis Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1471-6116","authenticated-orcid":false,"given":"Bharti","family":"Shah","sequence":"additional","affiliation":[{"name":"Novartis Pharmaceuticals Corporation  East Hanover New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6035-2054","authenticated-orcid":false,"given":"Oliver","family":"Pohl","sequence":"additional","affiliation":[{"name":"Novartis Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5773-091X","authenticated-orcid":false,"given":"Nicole","family":"Pezous","sequence":"additional","affiliation":[{"name":"Novartis Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8561-6735","authenticated-orcid":false,"given":"Thomas","family":"Faller","sequence":"additional","affiliation":[{"name":"Novartis Biomedical Research Novartis Pharma AG  Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,27]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-021-00556-y"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000012323"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/ml300396r"},{"issue":"4","key":"e_1_2_11_5_1","first-page":"168","article-title":"Siponimod (BAF312) Penetrates, Distributes, and Acts in the Central Nervous System: Preclinical Insights","volume":"7","author":"Bigaud M.","year":"2021","journal-title":"Mult Scler J Exp Transl Clin"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30475-6"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40263-020-00771-z"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.117.079574"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-018-0700-3"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1547"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-019-02729-7"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.5414\/CP202588"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-009-9088-1"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.036103"},{"key":"e_1_2_11_15_1","unstructured":"FDA \u201cClinical Drug Interaction Studies \u2014 Cytochrome P450 Enzyme\u2010 and Transporter\u2010Mediated Drug Interactions Guidance for Industry \u201d(2020)."},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2012.04400.x"},{"key":"e_1_2_11_17_1","unstructured":"Novartis \u201cMAYZENT (Siponimod) Prescribing Information \u201d(2019)."}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70657","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70657","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70657","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T12:52:25Z","timestamp":1784379145000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70657"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,27]]},"references-count":16,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1111\/cts.70657"],"URL":"https:\/\/doi.org\/10.1111\/cts.70657","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,27]]},"assertion":[{"value":"2026-01-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication 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