Vericiguat: a QTc interval study in patients with coronary artery disease
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BOETTCHER, M.-F., DUENGEN, H.-D., CORCEA, Vasile, DONATH, Frank, FUHR, Rainard, GAL, Pim, MIKUS, Gerd, TRENK, Dietmar, WERNER, Nils, PIRES, Philippe Vieira, MASCHKE, Claudia, ALIPRANTIS, Antonios Othon, BESCHE, Nina, BECKER, Corina. Vericiguat: a QTc interval study in patients with coronary artery disease. In: European Heart Journal, 2021, vol. 42, supl. nr. 1, p. 922. ISSN 0195-668X.
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European Heart Journal
Volumul 42, Supliment nr. 1 / 2021 / ISSN 0195-668X

Vericiguat: a QTc interval study in patients with coronary artery disease


Pag. 922-922

Boettcher M.-F.1, Duengen H.-D.2, Corcea Vasile3, Donath Frank4, Fuhr Rainard5, Gal Pim6, Mikus Gerd7, Trenk Dietmar8, Werner Nils9, Pires Philippe Vieira10, Maschke Claudia11, Aliprantis Antonios Othon12, Besche Nina13, Becker Corina1
 
1 Clinical Pharmacology, Wuppertal,
2 Berlin School of Public Health, Charité-Universitätsmedizin, Berlin,
3 ”Nicolae Testemițanu” State University of Medicine and Pharmacy,
4 SocraTec R and D GmbH, Erfurt,
5 Early Phase Clinical Unit, Berlin,
6 Centre for Human Drug Research, Leiden,
7 University Hospital Heidelberg,
8 University Medical Center Freiburg,
9 University Hospital Bonn,
10 Research and Development, Bayer AG, Wuppertal,
11 Study Management, Bayer AG, Wuppertal,
12 Translational Medicine, Merck and Co., Inc., New Jersey ,
13 Chrestos Concept GmbH and Co. KG, Essen
 
 
Disponibil în IBN: 30 martie 2024


Rezumat

Background: Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with ejection fraction less than 45% who had a previous decompensation event. Guidelines on QT studies recommend evaluation of investigational drugs at supratherapeutic exposures in healthy volunteers. We anticipated that supratherapeutic doses of vericiguat would decrease blood pressure. We conducted an adjusted QT study using the therapeutic range of vericiguat in patients with coronary artery disease (CAD), who were expected to be more haemodynamically stable with fewer confounders (e.g., on the electrocardiogram) than a HF population. Purpose: To assess the effect of vericiguat 10 mg once-daily on placeboadjusted change from baseline of the Fridericia-corrected QT interval (QTcF) in patients with stable CAD. Methods: This was a randomised, Phase Ib, placebo-controlled, double blind, double-dummy, multicentre study (NCT03504982). Test drug was vericiguat once-daily (up-titrated from 2.5 mg to 5 mg and then to 10 mg [treatments A, B, C] at 14-day intervals). The positive control was moxifloxacin 400 mg (single dose on Day 8 or Day 50 with placebo on other days [treatment D]; Figure). Patients were randomised to one of two sequences. We evaluated QTcF interval prolongation potential of vericiguat at increasing doses up to 10 mg, steady state. We investigated the pharmacokinetics, safety and tolerability of vericiguat. A clinically meaningful effect was defined as a QTcF change from baseline >10 ms relative to placebo. Assay sensitivity for moxifloxacin was confirmed by the lower limit of the 90% confidence interval (CI) of the time-matched, baseline-adjusted mean difference to placebo exceeding 5 ms at >1 time point. Results: A total of 74 patients (66 males and 8 females) with CAD, mean (standard deviation) age 63.4 (8.0) years, were included. Mean difference between vericiguat and placebo in QTcF change from baseline (≤7 h postdose) was <6 ms; no upper limit of the 90% CIs crossed the threshold of 10 ms. Lower limits of the two-sided 90% CI of the differences between moxifloxacin and placebo in QTcF change from baseline were >5 ms at 3 of 4 time points (Table). Peak plasma concentration (Cmax) of vericiguat following administration of vericiguat 10 mg was 322 μg/l and median time of maximum concentration (Tmax) was 4.5 h post-dose, in line with concentrations observed following administration of vericiguat 10 mg to patients with HF [1]. For moxifloxacin 400 mg, Cmax was 1960 μg/l and median Tmax was 3 h post-dose, in line with previously reported values [2]. Vericiguat up to 10 mg was generally safe and well tolerated. Conclusion: This study supports the assessment that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation. These data contribute to the overall safety profile of vericiguat for the treatment of patients with HF.

Cuvinte-cheie
plasma drug concentration, Electrocardiogram, chronic heart failure, pharmacotherapy, coronary arteriosclerosis, Steady state, QT interval, heart failure, blood pressure, exposure, adult, investigational new drugs, Germany, multicenter studies, randomization, safety, Guidelines, Pharmacokinetics, moxifloxacin, soluble guanylyl cyclase, therapeutic index, decompensation, ejection fraction, qtc, single-dose regimen, positive control, cmax, vericiguat