{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T13:45:18Z","timestamp":1770471918324,"version":"3.49.0"},"reference-count":26,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T00:00:00Z","timestamp":1757116800000},"content-version":"vor","delay-in-days":5,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"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":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The objective of this phase 1 study was to evaluate the pharmacokinetics (PK), pharmacodynamics, and cardiac effect following administration of ponesimod (a selective sphingosine\u20101\u2010phosphate receptor modulator) and propranolol in healthy adults. In treatment period (TP) 1, participants received ponesimod (2\u2009mg). In TP2, if resting heart rate (HR) was \u2265\u200955\u2009bpm, the ponesimod up\u2010titration regimen was initiated. Participants were randomized to TP2A (placebo plus ponesimod up\u2010titration) or TP2B (80\u2009mg propranolol plus ponesimod up\u2010titration). Concomitant administration resulted in an increased bradyarrhythmic effect on HR versus ponesimod alone. The mean maximum difference in mean hourly HR from time\u2010matched baseline for TP2B compared with TP2A during the first 12\u2009h post\u2010dose was \u221212.4\u2009bpm. This was observed after the first dose of ponesimod, persisted for the first 4 doses, then decreased to \u22127.4\u2009bpm post\u2010up\u2010titration. The lowest mean of the HR\n                    <jats:sub>nadir<\/jats:sub>\n                    in TP2B was 48.9\u2009bpm (95% CI: 46.4\u201351.3). There was no significant difference in the occurrence of 1st degree AV block between groups and no occurrences of 2nd or higher degree AV block. No clinically relevant changes were observed in the PK of ponesimod or propranolol. Overall, 88.5% of participants experienced \u2265\u20091 AE during the study. In TP2, the most reported TEAEs (\u2265\u20095%) considered related to ponesimod were fatigue (12 [25.5%]) and dizziness (10 [21.3%]). No deaths were reported. Co\u2010administration of ponesimod with propranolol resulted in a greater HR\u2010lowering effect compared to ponesimod alone, without significant changes in PK parameters or serious cardiac adverse events in healthy adults.\n                  <\/jats:p>","DOI":"10.1111\/cts.70341","type":"journal-article","created":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T07:50:41Z","timestamp":1757145041000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Randomized Trial on the Combined Effect of Ponesimod and Propranolol on Heart Rate, Cardiac Safety, and Pharmacokinetics in Healthy Adults"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9150-923X","authenticated-orcid":false,"given":"Sivi","family":"Ouwerkerk\u2010Mahadevan","sequence":"first","affiliation":[{"name":"Johnson &amp; Johnson  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tessa","family":"Hosman","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Leiden the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3079-6954","authenticated-orcid":false,"given":"Italo","family":"Poggesi","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Cologno Monzese Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Vets","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-4533","authenticated-orcid":false,"given":"Freya","family":"Rasschaert","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Beerse Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jay","family":"Ariyawansa","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaya","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Raritan New Jersey USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2656-9493","authenticated-orcid":false,"given":"Maroesja","family":"van Nimwegen\u2010Velthuis","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Leiden the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Vaclavkova","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-745X","authenticated-orcid":false,"given":"Juan Jose","family":"Perez\u2010Ruixo","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4262-7293","authenticated-orcid":false,"given":"Tatiana","family":"Sidorenko","sequence":"additional","affiliation":[{"name":"Johnson &amp; Johnson  Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,9,6]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-020711-075011"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02284"},{"key":"e_1_2_10_4_1","unstructured":"EMA Europa EU \u201cSummary of Product Characteristics \u201dhttps:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/ponvory\u2010epar\u2010product\u2010information_en.pdf. Ponvory\u2010epar\u2010product\u2010information accessed on 13 July 2023."},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01019-9"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm100181s"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/2040622315617354"},{"key":"e_1_2_10_8_1","unstructured":"FDA \u201cPONVORY (Ponesimod): US Prescribing Information \u201dTitusville NJ: Janssen Pharmaceuticals Inc. March 2021."},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-023-01308-5"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-013-7115-8"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-007-0448-4"},{"key":"e_1_2_10_12_1","unstructured":"Johnson & Johnson \u201cPONVORY (ponesimod): European Medicine Agency \u201dThe Janssen Pharmaceutical Companies of Johnson & Johnson 2021 accessed 15 July 2021."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0909494"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2010.208173"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12129"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2013-307282"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2827"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12778"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.820"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.281053"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/105294199277860"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1159\/000137311"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.4103\/0972-2327.83097"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/0009-9236(95)90231-7"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ahj.2014.06.028"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.5414\/CP202369"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.94.3.340"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70341","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70341","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70341","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T10:50:56Z","timestamp":1769683856000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":26,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1111\/cts.70341"],"URL":"https:\/\/doi.org\/10.1111\/cts.70341","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"2025-04-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-19","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70341"}}