{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T13:03:29Z","timestamp":1784811809964,"version":"3.55.0"},"reference-count":21,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100005646","name":"Actelion Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005646","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp;amp; Perspec"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The COVID\u201019 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate bioequivalence, using an adaptive study design, of tadalafil in fixed\u2010dose combination (FDC) tablets of macitentan\/tadalafil with single macitentan and tadalafil (Canadian\u2010sourced) tablets and assess the effect of food on FDC tablets in healthy subjects. This Phase 1, single\u2010center, open\u2010label, single\u2010dose, two\u2010part, two\u2010period, randomized, crossover study enrolled 62 subjects. Tadalafil bioequivalence as part of FDC of macitentan\/tadalafil (10\/40\u00a0mg) with single\u2010component tablets of macitentan (10\u00a0mg) and tadalafil (40\u00a0mg) was determined by pharmacokinetic (PK) assessment under fasted conditions. The effect of food on FDC was evaluated under fed and fasted conditions. Fasted 90% confidence intervals (CIs) for geometric mean ratios (GMRs) were within bioequivalence limits for tadalafil and macitentan. Fed and fasted 90% CIs for area under the curve (AUC) GMR were within bioequivalence limits. However, 90% CIs for maximum plasma concentration (\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    ) GMR for macitentan and tadalafil were outside bioequivalence limits. One FDC\u2010treated subject experienced a serious adverse event of transient ischemic attack (bioequivalence part). To address pandemic\u2010imposed limitations, an adaptive study design was implemented to demonstrate that the FDC tablet was bioequivalent to the free combination of macitentan and tadalafil (Canadian\u2010sourced). No clinically significant differences in PK were determined between fed and fasted conditions; the FDC formulation could be taken irrespective of meals. The FDC formulation under fasted and fed conditions was well tolerated with no clinically relevant differences in safety profiles between the treatment groups.\n                  <\/jats:p>\n                  <jats:p>NCT Number: NCT04235270.<\/jats:p>","DOI":"10.1002\/prp2.846","type":"journal-article","created":{"date-parts":[[2021,10,10]],"date-time":"2021-10-10T07:36:29Z","timestamp":1633851389000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bioequivalence and food effect of a fixed\u2010dose combination of macitentan and tadalafil: Adaptive design in the COVID\u201019 pandemic"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7797-2615","authenticated-orcid":false,"given":"D\u00e9nes","family":"Csonka","sequence":"first","affiliation":[{"name":"Actelion Pharmaceuticals Ltd Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladislav","family":"Fishman","sequence":"additional","affiliation":[{"name":"IQVIA RDS, Inc Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaya","family":"Natarajan","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Raritan New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Stieltjes","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Armas","sequence":"additional","affiliation":[{"name":"Celerion, Inc Tempe Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Dishy","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Raritan New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Jose","family":"Perez Ruixo","sequence":"additional","affiliation":[{"name":"Janssen Research and Development Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,10,8]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-115-5-343"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.10.031"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1213917"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1413687"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv317"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2019.11.041"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14347"},{"key":"e_1_2_13_9_1","unstructured":"Guidance on the conduct and analysis of comparative bioavailability studies.https:\/\/www.canada.ca\/content\/dam\/hc\u2010sc\/documents\/services\/drugs\u2010health\u2010products\/drug\u2010products\/applications\u2010submissions\/guidance\u2010documents\/bioavailability\u2010bioequivalence\/conduct\u2010analysis\u2010comparative.pdf"},{"key":"e_1_2_13_10_1","volume-title":"Adcirca [package insert]","year":"2008"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2005.02553.x"},{"key":"e_1_2_13_12_1","volume-title":"Opsumit [package insert]","year":"2013"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-011-1043-2"},{"key":"e_1_2_13_14_1","unstructured":"European Medicines Agency Evaluation of Medicines for Human Use CPMP. Guideline on the investigation of bioequivalence. CPMP\/QWP\/EWP\/1401\/98 Rev. 1. London.2010."},{"key":"e_1_2_13_15_1","unstructured":"Food and Drug Administration.Food\u2010effect bioavailability and fed bioequivalence studies. Guidance for Industry.2002.https:\/\/www.fda.gov\/files\/drugs\/published\/Food\u2010Effect\u2010Bioavailability\u2010and\u2010Fed\u2010Bioequivalence\u2010Studies.pdf. Accessed December 16 2020."},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/pst.294"},{"key":"e_1_2_13_17_1","unstructured":"Food and Drug Administration.Statistical approaches to establishing bioequivalence. Guidance for Industry.2001.https:\/\/www.fda.gov\/media\/70958\/download. Accessed May 11 2021."},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1121"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14748"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-015-0255-5"},{"key":"e_1_2_13_21_1","doi-asserted-by":"publisher","DOI":"10.1177\/0091270008315315"},{"key":"e_1_2_13_22_1","unstructured":"Adcirca FDA.Clinical pharmacology and biopharmaceutics review(s).https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2009\/022332s000_ClinPharmR.pdf. Accessed December 08 2020."}],"container-title":["Pharmacology Research &amp; Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.846","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/prp2.846","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/prp2.846","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T12:37:44Z","timestamp":1784810264000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1002\/prp2.846"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10]]},"references-count":21,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["10.1002\/prp2.846"],"URL":"https:\/\/doi.org\/10.1002\/prp2.846","archive":["Portico"],"relation":{},"ISSN":["2052-1707","2052-1707"],"issn-type":[{"value":"2052-1707","type":"print"},{"value":"2052-1707","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10]]},"assertion":[{"value":"2021-06-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00846"}}