Iyer, Ganesh, Darpo, Borje, Xue, Hongqi, Lecot, Jean, Zack, Julia, Bebrevska, Lidiya, Weis, Wendy and Drollmann, Anton Franz (2024) Concentration-QTcF modeling of Icenticaftor from a randomized, placebo- and positive-controlled thorough QT (TQT) study in healthy participants. Journal of cystic fibrosis :. pp. 1-13. ISSN 2160-763X

Abstract

Background: Icenticaftor (QBW251) is a potentiator of the cystic fibrosis transmembrane receptor (CFTR). Based on its mechanism of action, icenticaftor is expected to provide benefits in patients with COPD by restoring mucociliary clearance, which would eventually lead to a reduction of bacterial colonization and related inflammatory cascade.
Objective & Methods: A placebo- and positive-controlled, four-way cross-over TQT study was conducted in 46 healthy participants with the objective to assess the effect of therapeutic (300 mg twice daily for 6 days) and supra-therapeutic (750 mg twice daily for 6 days) oral doses of icenticaftor on ECG parameters, including concentration-QTc analysis. Moxifloxacin (400 mg, oral) was used as a positive control.
Results: In the primary concentration-QTc analysis performed on pooled data from Day 1 and Day 6 (steady state), the estimated population slope was shallow and slightly negative: -0.0012 ms/ng/mL (90%CI: -0.00135 to -0.00109). The effect on the QTcF interval (∆ΔQTcF) was predicted to be −1.33 ms (90% CI: −1.48 to -1.19) at the icenticaftor 300 mg b.i.d. peak concentration (geometric mean (GM) was 1093.5 ng/mL) and −5.52 ms (90%CI: −6.12 to −4.92) at 750 mg b.i.d peak concentration (GM Cmax was 4529.4 ng/mL) indicated a mild shortening effect of icenticaftor on QTcF interval length. The results of the by timepoint analysis indicated least squares (LS) placebo corrected mean ∆∆QTcF across time points ranged from -7.9 (90% CI: -10.11 to -5.78) to 0.1 ms (90% CI: -2.03 to 2.20) (at 1 and 24 hours post-dose both on Day 6) in the 750 mg dose group compared with -3.7 (90% CI: -5.35 to -1.97) to 1.6 ms (90% CI: -0.39 to 3.57) (at 1.5 and 24 hours post-dose both on Day 1) in the 300 mg dose group. Assay sensitivity was demonstrated with moxifloxacin.
Conclusion: The large accumulation of exposures especially the 4.3-fold increase in Cmax observed at the icenticaftor 750 mg b.i.d.compared to Icenticaftor 300 mg b.i.d. (2.3-fold) on Day 6 provided a large concentration range (up to 9540 ng/mL) to evaluate the effect of Icenticaftor on ΔΔQTcF. Based on the concentration QTc analysis, an effect on ΔΔQTcF

Item Type:	Article
Keywords:	thorough QT study icenticaftor cardiac repolorization
Date Deposited:	05 Mar 2024 00:46
Last Modified:	05 Mar 2024 00:46
URI:	https://oak.novartis.com/id/eprint/52106