Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Iberdomide

by Selleckchem | Aug 24 2023

Iberdomide is an orally available cereblon-modulating agent being developed for the treatment of hematologic malignancies and autoimmune-mediated diseases. To assess the potential concentration-QTc relationship in humans and to ascertain or exclude a potential QT effect by iberdomide, a plasma concentration and ΔQTcF (change from baseline of corrected QT interval using the Fridericia formula) model of iberdomide was developed. Iberdomide concentration and paired high-quality, intensive electrocardiogram signal from a single-ascending-dose study in healthy subjects (N = 56) were included in the analysis. The primary analysis was based on a linear mixed-effect model with ΔQTcF as the dependent variable; iberdomide plasma concentration and baseline QTcF as continuous covariates; treatment (active or placebo) and time as a categorical factor; and a random intercept per subject. The predicted change from baseline and placebo corrected (ΔΔQTcF) at the observed geometric mean maximum plasma concentration and 2-sided 90% confidence intervals at different dose levels were calculated. The upper bound of the 90% confidence interval of the model-predicted ΔΔQTcF effect at maximum concentration from the supratherapeutic dose of 6 mg (2.54 milliseconds) is <10-millisecond threshold, suggesting that iberdomide does not have a clinically relevant QT prolongation liability.

Comments:

It appears that you have provided a summary of a study conducted to assess the potential relationship between plasma concentration of iberdomide, a cereblon-modulating agent, and its effect on the corrected QT interval (QTc) in humans. The study included data from a single-ascending-dose study in healthy subjects, with a total of 56 participants.

The primary analysis of the study involved using a linear mixed-effect model to evaluate the change in QTc interval (ΔQTcF) as the dependent variable. The model included iberdomide plasma concentration and baseline QTcF as continuous covariates, treatment (active or placebo) and time as categorical factors, and a random intercept per subject.

Based on the analysis, the study found that at the observed geometric mean maximum plasma concentration of iberdomide, the predicted change from baseline and placebo-corrected ΔΔQTcF (change in ΔQTcF) had a 2-sided 90% confidence interval. The upper bound of this confidence interval at the supratherapeutic dose of 6 mg was less than a 10-millisecond threshold. This suggests that iberdomide does not have a clinically relevant QT prolongation liability, meaning it does not significantly affect the QT interval in a way that would be concerning for potential QT prolongation.

It's important to note that this summary is based on the information you provided and may not include all the details of the study. Additionally, as an AI language model, I don't have access to specific data or the ability to provide medical advice. If you have any further questions or require more detailed information, it would be best to consult the original study or reach out to a medical professional or researcher familiar with this topic.