Safety, pharmacodynamic, and pharmacokinetic characterization of vericiguat: results from six phase I studies in healthy
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CLINICAL TRIAL
Safety, pharmacodynamic, and pharmacokinetic characterization of vericiguat: results from six phase I studies in healthy subjects Michael Boettcher 1 & Dirk Thomas 2 & Wolfgang Mueck 3 & Stephanie Loewen 4 & Erich Arens 1,5 & Kenichi Yoshikawa 6 & Corina Becker 1,3 Received: 8 June 2020 / Accepted: 14 October 2020 # The Author(s) 2020
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 Keywords Heart failure . Pharmacotherapy . Phase I . Pharmacokinetic . Pharmacodynamic
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-020-03023-7) contains supplementary material, which is available to authorized users. * Corina Becker [email protected] 1
Research & Development, Pharmaceuticals, Clinical PD CV, Bayer AG, Wuppertal, Germany
2
Experimental Medicine, Bayer AG, Wuppertal, Germany
3
Research & Development, Pharmaceuticals, Clinical PK CV, Bayer AG, Aprather Weg 18a, 42113 Wuppertal, Germany
4
Chrestos Concept GmbH & Co. KG, Essen, Germany
5
Present address: Im Straesschen, Monheim, Germany
6
Clinical Sciences, Research & Development Japan, Bayer Yakuhin, Ltd, Osaka, Japan
Introduction Heart failure (HF) is a major healthcare burden [1, 2]. Three subtypes of HF exist: HF with preserved ejection fraction (HFpEF; left
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