Assessing QTc Effects of Vericiguat Using Two Different Concentration-QTc Modeling Approaches.
Clin Pharmacokinet
; 62(11): 1639-1648, 2023 11.
Article
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| MEDLINE
| ID: mdl-37672197
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Electrocardiografía
/
Compuestos Heterocíclicos con 2 Anillos
Tipo de estudio:
Clinical_trials
Límite:
Humans
Idioma:
En
Revista:
Clin Pharmacokinet
Año:
2023
Tipo del documento:
Article
País de afiliación:
Alemania