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 t1/2. 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…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 54 participants or records.
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