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

Koen Jolling, Angela Äbelö, Nicolas Luyckx, Marie-Anna Nandeuil, Mirco Govoni, Massimo Cella, Andreas Lindauer, Koen Jolling, Angela Äbelö, Nicolas Luyckx, Marie-Anna Nandeuil, Mirco Govoni, Massimo Cella, Andreas Lindauer

Abstract

Concentration-QTcF data obtained from two phase I studies in healthy volunteers treated with a novel phosphodiesterase-4 inhibitor currently under development for the treatment of chronic obstructive pulmonary disease were analyzed by means of mixed-effects modeling. A simple linear mixed-effects model and a more complex model that included oscillatory functions were employed and compared. The slope of the concentration-QTcF relationship was not significantly greater than 0 in both approaches, and the simulations showed that the upper limit of the 90% confidence interval around the mean ΔΔQTcF is not expected to exceed 10 ms within the range of clinically relevant concentrations. An additional simulation study confirmed the robustness of the simple linear mixed-effects model for the analysis of concentration-QT data and supported the modeling of data obtained from studies with different designs (parallel and crossover).

Conflict of interest statement

K.J., A.Ä., N.L., and A.L. were employed by SGS, a contract research organization that has received funding from Chiesi Farmaceutici. M.C., M‐A.N., and M.G. are employees of Chiesi Farmaceutici.

© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
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.
Figure 2
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.
Figure 3
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.
Figure 4
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.

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