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Abstract
Objective: This study was conducted to evaluate the effect of apremilast and its major metabolites on the placebo-corrected 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 double-blind treatment of apremilast, and an open-label, 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.
Highlights
Apremilast is an orally available compound approved for the treatment of active psoriatic arthritis (PsA) and moderate-tosevere plaque psoriasis
No trends or clinically meaningful changes were observed in clinical laboratory tests, vital signs, or ECG intervals throughout the study. This thorough QT/QTc study was performed in compliance with the principles of the International Conference on Harmonisation (ICH) E14 guidance and was designed to adequately assess any effect on QTc duration following multiple administration of apremilast at doses of 30 mg b.i.d. or 50 mg b.i.d. in healthy male subjects
The analyses showed that apremilast administered in multiple doses at 30 mg or 50 mg had little or no effect on QT/QTc interval
Summary
Apremilast is an orally available compound approved for the treatment of active psoriatic arthritis (PsA) and moderate-tosevere plaque psoriasis. Apremilast inhibits the phosphodiesterase 4 (PDE4) enzyme; PDE4 is the predominant cyclic adenosine monophosphate phosphodiesterase (cAMP). This inhibition of PDE4 causes a rise in intracellular cAMP levels and modulates expression of a wide array of inflammatory mediators [1, 2, 3, 4]. Recent clinical studies have shown that apremilast can be used in the treatment of PsA and psoriasis and has acceptable tolerability and safety profiles [5, 6, 7, 8, 9, 10]. All three are glucuronide metabolites and are not pharmacologically active [11]
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