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

## TL;DR

This study evaluated how givinostat, a drug for Duchenne muscular dystrophy, affects heart rhythms at normal and higher-than-recommended doses in healthy people.

## Contribution

The study provides new evidence on the QT interval effects of givinostat at therapeutic and supratherapeutic doses in healthy volunteers.

## Key findings

- Therapeutic doses of givinostat had a small, non-clinically relevant effect on QTcF intervals.
- Supratherapeutic doses caused mild QTc prolongation but remained within safe limits.
- An Emax model better described the concentration-QTc relationship than a linear model.

## Abstract

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 Tmax and the largest effect on the QTc interval was seen for both doses. In the concentration‐QTc analysis, an Emax 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.