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Clinically relevant covariates were assessed. Simulations were conducted to evaluate the impact of the lack of adherence to ponesimod treatment and provide guidance in cases of treatment re\u2010initiation. The maximal effect parameter of the PK\/HR model was lower in patients with MS (23.5% decrease) compared with healthy volunteers (43.2%). The effect of patient covariates on PK\/HR was similar to those identified in healthy participants and not clinically relevant in patients with MS. The population PK\/HR model well characterized the effect of ponesimod on the time course of HR in patients with MS. After 2\u2009weeks of treatment with 10\u2009mg or higher doses, the model indicated full tolerance development. After repeated dosing at 20\u2009mg, tolerance was maintained &gt;\u200960% of the steady\u2010state tolerance for up to 4\u2009days after the last dose. Re\u2010initiating with gradual uptitration is recommended if drug discontinuation lasts \u2265\u20094\u2009days. This managed the negative chronotropic effects of ponesimod. No bradycardia events were observed within the first 2\u2009weeks of treatment in patients with relapsing MS with a baseline HR &gt;\u200955\u2009bpm. This justifies the recommendation included in the human prescription drug labeling to monitor HR after the first ponesimod dose in these patients.<\/jats:p>","DOI":"10.1002\/cpt.2827","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T08:11:29Z","timestamp":1671178289000},"page":"692-703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pharmacokinetic\u2010Pharmacodynamic Modeling of the Ponesimod Effect on Heart Rate in Patients With Multiple Sclerosis"],"prefix":"10.1111","volume":"113","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2317-5028","authenticated-orcid":false,"given":"Bel\u00e9n","family":"Valenzuela","sequence":"first","affiliation":[{"name":"Janssen\u2010Cilag Spain, Part of Janssen Pharmaceutical Companies  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3079-6954","authenticated-orcid":false,"given":"Italo","family":"Poggesi","sequence":"additional","affiliation":[{"name":"Janssen\u2010Cilag Italy, Part of Janssen Pharmaceutical Companies  Cologno Monzese Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Luyckx","sequence":"additional","affiliation":[{"name":"SGS Exprimo NV  Mechelen Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Vaclavkova","sequence":"additional","affiliation":[{"name":"Actelion Pharmaceuticals Ltd, Part of Janssen Pharmaceutical Companies  Allschwil Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-745X","authenticated-orcid":false,"given":"Juan Jos\u00e9","family":"P\u00e9rez\u2010Ruixo","sequence":"additional","affiliation":[{"name":"Janssen\u2010Cilag Spain, Part of Janssen Pharmaceutical Companies  Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1401483"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2014.07.005"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458520970841"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/112.6.1419"},{"key":"e_1_2_10_5_1","volume-title":"PONVORY\u2122 (ponesimod): US Prescribing Information","year":"2021"},{"key":"e_1_2_10_6_1","volume-title":"PONVORY (ponesimod): European Medicine Agency","year":"2021"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12778"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.0405"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1124\/pr.54.2.265"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1358\/dnp.2004.17.6.829028"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12129"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.244"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2012.02061.x"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp021084"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.877"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcpt.12336"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40268-015-0095-7"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.820"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1159\/000368837"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.467"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2016.1196188"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2013-307282"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01020-2"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-021-01019-9"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1023\/B:JOPA.0000012998.04442.1f"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01061469"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-011-9255-z"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.40.1.67"},{"key":"e_1_2_10_29_1","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Development Core Team","year":"2009"},{"key":"e_1_2_10_30_1","unstructured":"Bauer R.J.ICON Development Solutions. 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