Safety, pharmacodynamic, and pharmacokinetic characterization of vericiguat: results from six phase I studies in healthy subjects

Michael Boettcher,Kenichi Yoshikawa,Wolfgang Mueck,Erich Arens,Corina Becker,Dirk Thomas,Stephanie Loewen

doi:10.1007/s00228-020-03023-7

Michael Boettcher, Kenichi Yoshikawa + Show 5 more

Open Access

https://doi.org/10.1007/s00228-020-03023-7

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Abstract

PurposeTo characterize the safety, pharmacodynamics, and pharmacokinetics (PK) of vericiguat in healthy males.MethodsSix 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.ResultsOverall, 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.ConclusionIn general, vericiguat was well tolerated. These results supported further clinical evaluation of vericiguat QD in patients with heart failure.Registry numbersEudraCT: 2011-001627-21; EudraCT: 2012-000953-30

Highlights

Heart failure (HF) is a major healthcare burden [1, 2]
Despite the availability of current treatments shown to improve survival in HF with reduced ejection fraction (HFrEF) [3], around one in six patients with chronic HFrEF will experience a worsening HF event, and this segment of patients is at high risk for mortality and recurrent hospitalization for HF [4]
The pathophysiology of HF involves multiple systems, including the sympathetic nervous system and the renin–angiotensin–aldosterone system [5], which are the targets of current treatment [6]

Summary

Introduction

Heart failure (HF) is a major healthcare burden [1, 2]. Despite the availability of current treatments shown to improve survival in HFrEF [3], around one in six patients with chronic HFrEF will experience a worsening HF event, and this segment of patients is at high risk for mortality and recurrent hospitalization for HF [4]. The pathophysiology of HF involves multiple systems, including the sympathetic nervous system and the renin–angiotensin–aldosterone system [5], which are the targets of current treatment [6]. Eur J Clin Pharmacol (2021) 77:527–537 guanosine monophosphate (NO–sGC–cGMP) signaling contributes to cardiac function [6]. Impairment of the NO– sGC–cGMP signaling pathway is implicated in cardiovascular, cardiopulmonary, and cardiorenal diseases [6]

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