The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study

Abstract

Objective: This study was conducted to evaluate the effect of apremilast and its major metabolites on the placebocorrected change-from-baseline QTc interval of an electrocardiogram (ECG).

Materials and methods: Healthy male subjects received each of 4 treatments in a randomized, crossover manner. In the 2 active treatment periods, apremilast 30 mg (therapeutic exposure) or 50 mg (supratherapeutic exposure) was administered twice daily for 9 doses. A placebo control was used to ensure doubleblind treatment of apremilast, and an openlabel, single dose of moxifloxacin 400 mg was administered as a positive control. ECGs were measured using 24-hour digital Holter monitoring.

Results: The two-sided 98% confidence intervals (CIs) for ΔΔQTcI of moxifloxacin completely exceeded 5 ms 2 - 4 hours postdose. For both apremilast dose studies, the least-squares mean ΔΔQTcI was < 1 ms at all time points, and the upper limit of two-sided 90% CIs was < 10 ms. There were no QT/QTc values > 480 ms or a change from baseline > 60 ms. Exploratory evaluation of pharmacokinetic/pharmacodynamic data showed no trend between the changes in QT/QTc interval and the concentration of apremilast or its major metabolites M12 and M14.

Conclusions: Apremilast did not prolong the QT interval and appears to be safe and well tolerated up to doses of 50 mg twice daily.

Figure 1.. Mean (+ SD) plasma concentration of (A) apremilast, (B) M12, and (C) M14 by time and treatment on day 5 (semi-logarithmic scale). b.i.d. = twice daily.

Figure 2.. Change from baseline and placebo-corrected QTcI vs. time: (A) moxifloxacin 400 mg mean two-sided 98% CI and apremilast (B) 30 mg b.i.d. and (C) 50 mg b.i.d. mean two-sided 90% CI. CI = confidence interval; QTcI = QT interval using an individual correction method.

Figure 3.. Pooled change from baseline and placebo-corrected QTcI interval vs. (A) apremilast, (B) M12, and (C) M14 concentrations. QTcI = QT interval using an individual correction method.