Thorough QT Study on the Effect of Therapeutic and Supratherapeutic Dosing of Givinostat in Healthy Volunteers.

A small, clinically non-relevant effect on QTcF was observed after therapeutic givinostat 100-mg dose.

• Mean placebo-corrected, change-from-baseline QTcF (ΔΔQTcF) was 5.5 ms after the 100-mg therapeutic dose.
• 5.5 ms is below the 10 ms threshold considered clinically relevant for QTc prolongation.
• A delay of approximately 3 hours between Tmax and the largest effect on the QTc interval was observed.

Clinically relevant QTc prolongation was observed with the supratherapeutic dose of 300 mg givinostat.

• The supratherapeutic 300-mg dose produced a mild ΔΔQTcF increase of 13.6 ms.
• 13.6 ms exceeds the 10 ms threshold considered clinically relevant for QTc prolongation.
• A delay of approximately 3 hours between Tmax and the largest effect on the QTc interval was also seen with the supratherapeutic dose.

An Emax model described the concentration-QTc relationship better than the prespecified linear model.

• The concentration-QTc analysis used both a prespecified linear model and an Emax model.
• The Emax model captured the data better than the prespecified linear model.
• The Emax model showed that an effect on ΔΔQTcF exceeding 10 ms could be excluded within the full range of observed givinostat concentrations in the study and up to approximately 745 ng/mL.

Givinostat at the maximum labeled dose for DMD is not expected to pose a QT prolongation risk.

• The maximum labeled dose for DMD is up to 53.2 mg twice daily.
• The therapeutic dose studied (100 mg single dose) produced only a clinically non-relevant ΔΔQTcF of 5.5 ms.
• The concentration-QTc Emax model supported the conclusion that QTc effects exceeding 10 ms could be excluded at concentrations expected with clinical DMD dosing.

The study used a four-way crossover design with a positive control to evaluate givinostat's cardiac effects.

• Healthy volunteers received each treatment according to a block randomization scheme.
• Four treatments were evaluated: givinostat 100 mg (therapeutic dose), givinostat 300 mg (supratherapeutic dose), placebo oral suspension, and moxifloxacin 400 mg oral tablet (positive control).
• Cardiodynamic assessments were paired with pharmacokinetic samples.
• Givinostat was administered as a hydrochloride monohydrate oral suspension.

Givinostat is a class I/II histone deacetylase inhibitor indicated for Duchenne muscular dystrophy.

• Givinostat inhibits both class I and class II histone deacetylase enzymes.
• The approved indication is Duchenne muscular dystrophy (DMD).
• The maximum labeled dose for DMD is up to 53.2 mg twice daily.