Abemaciclib does not increase the corrected QT interval in healthy participants

Area of Science:

• Pharmacology
• Cardiology
• Oncology

Background:

• Abemaciclib is an oral cyclin-dependent kinases 4 and 6 inhibitor used for advanced breast cancer.
• Cardiac repolarization, specifically the QTc interval, is a critical safety parameter for drug development.

Purpose of the Study:

• To evaluate the effect of abemaciclib and its active metabolites (M2, M20) on the QTc interval using an exposure-response model.
• To assess the safety and tolerability of single ascending doses of abemaciclib in healthy volunteers.

Main Methods:

• A single-blind, randomized, placebo-controlled study involving 35 healthy participants.
• Administration of single oral doses of abemaciclib (200-600mg) with serial ECG and pharmacokinetic sampling.
• Exposure-response analysis to correlate drug/metabolite concentrations with QTc changes (ΔΔQTcF).

Main Results:

• No statistically significant relationship was found between abemaciclib/metabolite concentrations and placebo-corrected QTc changes (ΔΔQTcF).
• The slopes of ΔΔQTcF for abemaciclib, its metabolites, and total analyte concentrations were not significantly different from zero.
• Abemaciclib was well-tolerated up to 400mg; the 600mg dose led to increased gastrointestinal adverse events.

Conclusions:

• Single doses of abemaciclib up to 400mg do not cause clinically relevant QTc interval prolongation in healthy individuals.
• Abemaciclib demonstrates a favorable cardiac safety profile at doses up to 400mg, with gastrointestinal effects being dose-limiting at higher exposures.