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- Title
Safety, pharmacodynamic, and pharmacokinetic characterization of vericiguat: results from six phase I studies in healthy subjects.
- Authors
Boettcher, Michael; Thomas, Dirk; Mueck, Wolfgang; Loewen, Stephanie; Arens, Erich; Yoshikawa, Kenichi; Becker, Corina
- Abstract
Purpose: To characterize the safety, pharmacodynamics, and pharmacokinetics (PK) of vericiguat in healthy males. Methods: Six phase I studies were conducted in European, Chinese, and Japanese males. Subjects received oral vericiguat as a single dose (0.5–15.0 mg solution [for first-in-human study] or 1.25–10.0 mg immediate release [IR tablets]) or multiple doses (1.25–10.0 mg IR tablets once daily [QD] or 5.0 mg IR tablets twice daily for 7 consecutive days). Bioavailability and food effects on vericiguat PK (IR tablets) were also studied in European subjects. Results: Overall, 255 of 265 randomized subjects completed their respective studies. There were no deaths or serious adverse events. Vericiguat was generally well tolerated at doses ≤ 10.0 mg. In the first-in-human study, the most frequent drug-related adverse events were headache and postural dizziness (experienced by five subjects each [7.2%]). Three of four subjects who received vericiguat 15.0 mg (oral solution, fasted) experienced orthostatic reactions. Vericiguat (≤ 10.0 mg, IR tablets) was rapidly absorbed (median time to reach maximum plasma concentration ≤ 2.5 h [fasted]) with a mean half-life of about 22.0 h (range 17.9–27.0 h for single and multiple doses). No evidence for deviation from dose proportionality or unexpected accumulation was observed. Administration of vericiguat 5.0 mg IR tablets with food increased bioavailability by 19% (estimated ratio 119% [90% confidence interval]: 108; 131]), reduced PK variability, and prolonged vericiguat absorption relative to the fasted state. Conclusion: In general, vericiguat was well tolerated. These results supported further clinical evaluation of vericiguat QD in patients with heart failure. Registry numbers: EudraCT: 2011-001627-21; EudraCT: 2012-000953-30
- Subjects
CONFIDENCE intervals; DRUG tolerance; HETEROCYCLIC compounds; BIOAVAILABILITY; RANDOMIZED controlled trials; DESCRIPTIVE statistics; STATISTICAL sampling; PATIENT safety; HEART failure
- Publication
European Journal of Clinical Pharmacology, 2021, Vol 77, Issue 4, p527
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-020-03023-7