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

Abstract

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.

• Authors: Yiming Cheng, Allison Gaudy, Liangang Liu, Ying Ye, Michael Thomas, Yongjun Xue, Simon Zhou, Yan Li
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 12 Issue 8 Pg. 819-825 (08 2023) ISSN: 2160-7648 [Electronic] United States
• PMID: 37079714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023, The American College of Clinical Pharmacology.

Chemical References

• Moxifloxacin
• Fluoroquinolones
• iberdomide

Topics

• Humans
• Moxifloxacin (pharmacology)
• Fluoroquinolones (pharmacology)
• Double-Blind Method
• Heart Rate
• Dose-Response Relationship, Drug