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

Givinostat is a class I/II histone deacetylase inhibitor indicated for Duchenne muscular dystrophy (DMD). The study evaluated the effect of therapeutic and supratherapeutic givinostat doses on the QT/QTc interval. Healthy volunteers received each treatment—givinostat hydrochloride monohydrate oral suspension as a therapeutic (100 mg) or supratherapeutic (300 mg) dose, placebo oral suspension, or moxifloxacin oral tablet (positive control, 400 mg)—according to a block randomization scheme. Cardiodynamic assessments were paired with pharmacokinetic samples. A small, clinically non‐relevant effect on mean placebo‐corrected, change‐from‐baseline QTcF (∆∆QTcF) of 5.5 ms was seen after givinostat 100‐mg dose. Clinically relevant QTc prolongation was observed with the supratherapeutic dose, with a mild ∆∆QTcF increase of 13.6 ms. A delay of ≈3 h between T max and the largest effect on the QTc interval was seen for both doses. In the concentration‐QTc analysis, an E max model captured the data better than the prespecified linear model and showed that an effect on ∆∆QTcF exceeding 10 ms could be excluded within the full range of observed givinostat concentrations in this study and up to ≈745 ng/mL. Givinostat at the maximum labeled dose (up to 53.2 mg twice daily for DMD) is not expected to pose a QT prolongation risk.