Evaluation of the Effect of Selumetinib on Cardiac Repolarization: A Randomized, Placebo- and Positive-controlled Crossover QT/QTc Study in Healthy Subjects

Abstract

Purpose: Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective allosteric mitogen-activated protein kinase 1/2 inhibitor with a short t_1/2. The purpose of this study was to characterize the effect of selumetinib on cardiac repolarization and a potential exposure-QT effect relationship.

Methods: A double-blind (selumetinib), randomized, 3-period crossover study was conducted to assess the effects of a single oral dose of selumetinib (75 mg) on the QTc interval compared with placebo, using moxifloxacin as an open-label positive control, in healthy male subjects aged 18 to 45 years. QT intervals were evaluated by using the Fridericia formula (QTcF) and the Bazett formula. Further analysis was conducted by using nonlinear mixed effects modeling to characterize any relationship between selumetinib exposure and QTc and was used to predict the effect if selumetinib 150 mg was administered. All adverse events were characterized and recorded.

Findings: A total of 54 healthy male subjects were enrolled, and 48 completed all treatments. Mean age was 27 years; four subjects were of Hispanic or Latino ethnicity, and 53.7% were White and 46.3% were Black. The BMI of subjects ranged from 19.4 to 29.6 kg/m². After a single oral dose of selumetinib 75 mg, the highest upper bound of the 2-sided 90% CI for placebo-corrected, baseline-adjusted QTcF (ΔΔQTcF) over the 24-hour postdose measurement interval was 2.5 milliseconds, which was well below the 10-millisecond upper bound for concluding no effect. The relationship between ΔΔQTcF and selumetinib concentrations was adequately described by using a nonlinear mixed effect model. The mean estimated ∆∆QTcF interval prolongation based on the geometric mean C_max of 75 mg selumetinib was 2.38 milliseconds (90% CI, 1.25 to 3.52), which was in good agreement with the statistical analysis results. The model also predicted mean ∆∆QTcF interval prolongations of 4.70 milliseconds (90% CI, 2.46 to 6.95) after a single supratherapeutic dose of selumetinib 150 mg, indicating the upper bound of 2-sided 90% CIs for ΔΔQTcF are predicted to be <10 milliseconds. Selumetinib, administered as a single 75 mg oral dose, was generally safe and well tolerated.

Implications: Selumetinib 75 mg did not cause any QT/QTc interval prolongation in these healthy subjects, and selumetinib is not expected to have a clinically relevant effect on cardiac repolarization in patients at the anticipated therapeutic dose of 75 mg. The model also demonstrated the low potential for any QTc effects of selumetinib at doses higher than the standard therapeutic dose.

Keywords: QTc; cardiac repolarization; pharmacodynamics; pharmacokinetics; selumetinib.