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

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.