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In the SRD trial (NCT02694354; February 29, 2016), within each of the three dose groups (DGs), six subjects received BI\u00a0685509 (1.0, 2.5, or 5.0\u00a0mg) and two received placebo (<jats:italic>N<\/jats:italic>\u2009=\u200924). In the MRD trial (NCT03116906; April\u00a017, 2017), within each of the five DGs, nine subjects received BI\u00a0685509 (uptitrated to 1\u00a0mg once daily [qd; DG1], 2.5\u00a0mg twice daily [DG2], 5.0\u00a0mg qd [DG3]; 3.0\u00a0mg three times daily [tid; DG4] or 4.0\u00a0mg tid [DG5]) and three received placebo, for 14\u201317\u00a0days (<jats:italic>N<\/jats:italic>\u2009=\u200960). In the SRD trial, 7\/24 subjects (29.2%) had\u2009\u2265\u20091 adverse event (AE), most frequently orthostatic dysregulation (<jats:italic>n<\/jats:italic>\u2009=\u20094). In the MRD trial, 26\/45 subjects (57.8%) receiving BI\u00a0685509 had\u2009\u2265\u20091 AE, most frequently orthostatic dysregulation and fatigue (each <jats:italic>n<\/jats:italic>\u2009=\u200912). Tolerance development led to a marked decrease in orthostatic dysregulation events (DG3). BI\u00a0685509 was rapidly absorbed after oral administration, and exposure increased in a dose-proportional manner after single doses. Multiple dosing resulted in near\u2013dose-proportional increase in exposure and limited accumulation. BI\u00a0685509 pharmacokinetics appeared linear with time; steady state occurred 3\u20135\u00a0days after each multiple-dosing period. Increased plasma cyclic guanosine monophosphate and decreased blood pressure followed by a compensatory increase in heart rate indicated target engagement. BI\u202f685509 was generally well tolerated; orthostatic dysregulation may be appropriately countered by careful uptitration.<\/jats:p>","DOI":"10.1007\/s00210-024-03165-w","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T20:20:53Z","timestamp":1716582053000},"page":"8101-8116","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Safety, tolerability, pharmacokinetics, and pharmacodynamics of BI\u00a0685509, a soluble guanylyl cyclase activator, in healthy volunteers: Results from two randomized controlled trials"],"prefix":"10.1007","volume":"397","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9330-872X","authenticated-orcid":false,"given":"Diane","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4460-5867","authenticated-orcid":false,"given":"Friedeborg","family":"Seitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Giessmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0277-8134","authenticated-orcid":false,"given":"Friedrich","family":"Schulze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,24]]},"reference":[{"key":"3165_CR1","unstructured":"Aktories K, F\u00f6rstermann, U, Hofmann, F, Starke K (2013) Allgemeine und spezielle Pharmakologie und Toxikologie, 11th edn. 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Subsequently, the Federal Institute for Drugs and Medical Devices (Bundesinstitut f\u00fcr Arzneimittel und Medizinprodukte, Bonn, Germany) reviewed and approved both studies. Both studies were conducted in accordance with the principles of the Declaration of Helsinki, the International Conference on Harmonisation \u2013 Good Clinical Practice, applicable regulatory requirements, and standard operating procedures of the trial sponsor.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All subjects provided written informed consent prior to participation.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}},{"value":"Diane Wong, Verena Bauer, Thomas Giessmann, and Friedrich Schulze are employees of Boehringer Ingelheim. Friedeborg Seitz is an employee of CRS Clinical Research Services.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}