Safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509, a soluble guanylyl cyclase activator, in healthy volunteers: Results from two randomized controlled trials.
Cyclic guanosine monophosphate signaling
Pharmacodynamics
Pharmacokinetics
Soluble guanylate cyclase activator
Vasodilatory-stimulated phosphoprotein
Journal
Naunyn-Schmiedeberg's archives of pharmacology
ISSN: 1432-1912
Titre abrégé: Naunyn Schmiedebergs Arch Pharmacol
Pays: Germany
ID NLM: 0326264
Informations de publication
Date de publication:
24 May 2024
24 May 2024
Historique:
received:
04
03
2024
accepted:
13
05
2024
medline:
25
5
2024
pubmed:
25
5
2024
entrez:
24
5
2024
Statut:
aheadofprint
Résumé
This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 685509 after oral single rising doses (SRDs) or multiple rising doses (MRDs) in healthy volunteers. In the SRD trial (NCT02694354; February 29, 2016), within each of the three dose groups (DGs), six subjects received BI 685509 (1.0, 2.5, or 5.0 mg) and two received placebo (N = 24). In the MRD trial (NCT03116906; April 17, 2017), within each of the five DGs, nine subjects received BI 685509 (uptitrated to 1 mg once daily [qd; DG1], 2.5 mg twice daily [DG2], 5.0 mg qd [DG3]; 3.0 mg three times daily [tid; DG4] or 4.0 mg tid [DG5]) and three received placebo, for 14-17 days (N = 60). In the SRD trial, 7/24 subjects (29.2%) had ≥ 1 adverse event (AE), most frequently orthostatic dysregulation (n = 4). In the MRD trial, 26/45 subjects (57.8%) receiving BI 685509 had ≥ 1 AE, most frequently orthostatic dysregulation and fatigue (each n = 12). Tolerance development led to a marked decrease in orthostatic dysregulation events (DG3). BI 685509 was rapidly absorbed after oral administration, and exposure increased in a dose-proportional manner after single doses. Multiple dosing resulted in near-dose-proportional increase in exposure and limited accumulation. BI 685509 pharmacokinetics appeared linear with time; steady state occurred 3-5 days 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 685509 was generally well tolerated; orthostatic dysregulation may be appropriately countered by careful uptitration.
Identifiants
pubmed: 38789635
doi: 10.1007/s00210-024-03165-w
pii: 10.1007/s00210-024-03165-w
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
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