Concentration–QT Modeling Following Inhalation of the Novel Inhaled Phosphodiesterase‐4 Inhibitor CHF6001 in Healthy Volunteers Shows an Absence of QT Prolongation

Figures

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  Figure 1. Visual predictive check of the linear mixed‐effect model. Solid lines are the 10th and 90th (blue) and 50th (red) percentiles of the observed data, and the shaded areas are the 95% confidence intervals around the corresponding percentiles of the predictions. Observed and simulated ∆QTcF data were prediction corrected (predcorr) before plotting. FIH, first in human; h, hour; MAD, multiple‐ascending dose; SAD, single‐ascending dose.

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  Figure 2. Visual predictive check of the cosine model. Solid lines are the 10th and 90th (blue) and 50th (red) percentiles of the observed data, and the shaded areas are the 95% confidence intervals around the corresponding percentiles of the predictions. Observed and simulated QTcF data were prediction corrected (predcorr) before plotting. FIH, first in human; h, hour; MAD, multiple‐ascending dose; SAD, single‐ascending dose.

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  Figure 3. Simulation of the concentration–ΔΔQTcF relationship using the cosine model. The vertical lines indicate the geometric mean peak plasma concentration at steady state observed with twice‐daily (bid) dosing using the NEXThaler device in the Extension study. The gray area is the 90% confidence interval. The red vertical line marks the concentration at which the upper limit of the 90% confidence interval is predicted to cross the 10‐milliseconds limit.

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  Figure 4. Rate of false positive study outcomes when simulated with the cosine (COS) model and a true slope of 0 or 0.00081 ms/pg/mL (corresponding to an average increase in QTcF of 5 ms at the peak plasma concentration following twice‐daily dosing of 2.4 mg). The labels on each panel indicate the design (single‐ascending dose (SAD) or multiple‐ascending dosing (MAD)) and the number of participants. LME, linear mixed effect.