PP163—PBMC Increase Sirtuin3 Protein Expression in Acute Adaptation to Hypoxia in Humans

Abstract

2013 e69 for moxifloxacin on day 1 and day 24. In treatment group B, placebo for ponesimod was administered once daily for 22 days (days 2–23). In addition, subjects received a single oral dose of moxifloxacin 400 mg either on day 1 or day 24. Replicate ECGs were to be extracted from the continuous digital 12-lead ECG recording over 12 hours. Primary end point was the baseline-adjusted, placebo-corrected effect of individual nonlinear corrected QT intervals (Δ Δ QTcI) on day 12 (40 mg) and on day 23 (100 mg). The relationship between plasma concentrations of ponesimod and metabolites and Δ Δ QTcI was assessed by applying a linear mixed effects modeling approach. Results: Ponesimod caused a small QTc prolongation, with a mean peak effect on Δ Δ QTcI of 6.9 ms (upper bound of the 2-sided 90% CI, 11.3 ms) on 40 mg and 9.1 ms (upper bound of the 2-sided 90% CI, 14.0 ms) on 100 mg. However, upon extrapolation to steady-state concentrations reached with 20-mg ponesimod, the upper bound of the 2-sided 90% CI would be below 10 ms, and should result in a negative study for doses of 20-mg ponesimod or lower. There was no relevant increased incidence of QTcI outliers, either as absolute or change from baseline, and QTcI > 480 ms or QTcI increase > 60 ms from baseline was not observed with ponesimod. Ponesimod did not affect the PR or QRS intervals. Assay sensitivity was demonstrated by moxifloxacin QTcI response with a mean peak effect on Δ Δ QTcI of 11.8 ms (lower bound of the 2-sided 90% CI, 9.0 ms). Conclusion: Ponesimod at doses of 40 mg and 100 mg causes a small QTc prolongation. However, based on the concentration-effect relationship no clinically relevant effect on QTc interval is expected for a dose of 20 mg, the highest selected dose for Phase 3. Disclosure of Interest: M. Hoch: Shareholder of Actelion Pharmaceuticals Ltd, employee of Actelion Pharmaceuticals Ltd. A. Vaclavkova: Shareholder of Actelion Pharmaceuticals Ltd, employee of Actelion Pharmaceuticals Ltd. R. Stoltz: Employee of Covance Clinical Research Unit, Evansville. P. Brossard: Shareholder of Actelion Pharmaceuticals Ltd, employee of Actelion Pharmaceuticals Ltd. J. Dingemanse: Shareholder of Actelion Pharmaceuticals Ltd, employee of Actelion Pharmaceuticals Ltd.