The effect of the glucosylceramide synthase inhibitor lucerastat on cardiac repolarization: results from a thorough QT study in healthy subjects

Figures

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  Fig. 1. Plasma concentration–time profiles of lucerastat. Exposure to lucerastat increased approximately dose-proportionally and was characterized by rapid absorption and quick elimination. a Healthy male subjects after administration of 2000 and 4000 mg in Part A (N = 6). b Healthy male and female subjects after administration of 1000 and 4000 mg in Part B (N = 36). Data expressed as arithmetic mean (+ SD). N, number of subjects in the population; SD, standard deviation

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  Fig. 2. Change-from-baseline in HR across time points and study treatments. Mean ΔHR on lucerastat and moxifloxacin closely followed the pattern observed on placebo. a Effect of study treatments on ΔHR. b Effect of study treatments on ΔΔHR. Data expressed as LS mean and 90% CI based on a linear mixed-effects model. bpm, beats per minute; CI, confidence interval; Δ, change-from-baseline; ΔΔ, placebo-corrected change-from-baseline; HR, heart rate; LS, least squares

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  Fig. 3. Change-from-baseline in QTcF across time points and study treatments. Mean ΔQTcF on lucerastat closely followed the pattern observed on placebo with no indication of dose dependency, whereas moxifloxacin caused a clear QTc prolongation. a Effect of study treatments on ΔQTcF. b Effect of study treatments on ΔΔQTcF. Data expressed as LS mean and 90% CI based on a linear mixed-effects model. The dashed black lines represent the threshold for clinically concerning QTc prolongation. CI, confidence interval; Δ, change-from-baseline; ΔΔ, placebo-corrected change-from-baseline; LS, least squares; QTcF, Fridericia-corrected QTc

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  Fig. 4. Concentration-QTc analysis. A linear model with a treatment effect-specific intercept was fitted for lucerastat and moxifloxacin plasma concentrations. For lucerastat, a QTcF effect above 10 ms could be excluded up to a plasma concentration of approximately 34 μg/mL, whereas moxifloxacin caused a clear QTc prolongation. a Lucerastat and b moxifloxacin. Left panel: scatter plots of observed plasma concentrations and estimated placebo-adjusted ΔQTcF by subject. The solid red lines with dashed red lines denote the predicted mean ΔΔQTcF with 90% CI. The blue squares, red triangles, and black circles denote the pairs of observed lucerastat plasma concentrations and estimated placebo-adjusted ΔQTcF by subject for lucerastat 1000 mg, lucerastat 4000 mg, and placebo, respectively (a). The green diamonds and black circles denote the pairs of observed moxifloxacin plasma concentrations and estimated placebo-adjusted ΔQTcF by subject for moxifloxacin and placebo, respectively (b). Right panel: relationship between lucerastat (a) and moxifloxacin (b) plasma concentrations and predicted ΔΔQTcF. The solid black lines with gray shaded area denote the predicted mean (90% CI) ΔΔQTcF. The blue,…