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

Abstract

AbstractIberdomide 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.