Dataset Information

Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.

ABSTRACT:

Background and objectives

Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure. A dedicated QTc study in patients with chronic coronary syndromes demonstrated no clinically relevant QTc effect of vericiguat for exposures across the therapeutic dose range (2.5-10 mg). Interval prolongation concentration-QTc (C-QTc) modeling was performed to complement the statistical evaluations of QTc in the dedicated QTc study.

Methods

Individual time-matched, baseline- and placebo-corrected Fridericia-corrected QT interval values (ΔΔQTcF) were derived. Two approaches for ΔΔQTcF calculation were investigated: (1) ΔΔQTcF correction with data from a single baseline (as in the primary statistical analysis); and (2) ΔΔQTcF correction with a modeled baseline (considering all available individual non-treatment baselines). The ΔΔQTcF values were related to observed vericiguat concentrations with linear mixed-effects modeling.

Results

For both modeling approaches, a positive relationship was found between ΔΔQTcF and vericiguat concentration; however, the slope for the single-baseline approach was not statistically significant, whereas the slope from the modeled-baseline approach was statistically significant. The upper bound of the two-sided 90% confidence interval for model-derived QTc was < 10 ms at the highest observed exposure (745 μg/L; investigated dose range 2.5-10 mg).

Conclusion

By applying a single-baseline approach and a modeled-baseline approach that integrated all available QTc data across doses to characterize the QTc prolongation potential, this study showed that vericiguat 2.5-10 mg is not associated with clinically relevant QTc effects, in line with the conclusion from the primary statistical analysis.

Clinical trials registration number

ClinicalTrials.gov NCT03504982.

SUBMITTER: Ruehs H

PROVIDER: S-EPMC10581916 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Publications

Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.

Ruehs Hauke H Solms Alexander A Frei Matthias M Becker Corina C Trujillo Maria E ME Garmann Dirk D Meyer Michaela M

Clinical pharmacokinetics 20230906 11

<h4>Background and objectives</h4>Vericiguat is a soluble guanylate cyclase stimulator indicated to reduce the risk of cardiovascular death and hospitalization due to heart failure. A dedicated QTc study in patients with chronic coronary syndromes demonstrated no clinically relevant QTc effect of vericiguat for exposures across the therapeutic dose range (2.5-10 mg). Interval prolongation concentration-QTc (C-QTc) modeling was performed to complement the statistical evaluations of QTc in the ded ...[more]

PMID: 37672197

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Dataset Information

Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.

Background and objectives

Methods

Results

Conclusion

Clinical trials registration number

Publications

Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.

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