Background: Givinostat is an oral histone deacetylase inhibitor indicated for Duchenne muscular dystrophy in patients aged ≥6 years. In the phase 3 EPIDYS study, a weight-based starting dose and flexible treatment regimen allowed dose adjustments for low platelet levels. Higher givinostat exposures initially occurred in heavier patients, but dose reductions led to similar exposures.
Objectives: To evaluate a simplified regimen that reduced the number of weight-based dosing groups from 9 to 4 and modified doses for higher-weight patients.
Methods: A pharmacometric simulation based on pharmacokinetic/pharmacodynamic data from EPIDYS was conducted using virtual pediatric patients stratified by weight (n=1000/group). Simulated platelet counts were assessed biweekly; if predicted values were <150 × 10⁹/L, dose reductions were applied. Results: Simulated givinostat exposures were comparable in the 10–20 kg and 20–40 kg groups (area under the curve (AUC)₀₋₁₂: 385 and 434 hr•ng/mL) but slightly higher in the 40–60 kg and >60 kg groups (AUC₀₋₁₂ 504 and 536 hr•ng/mL) following the first administration. At steady state, following final dose modifications, simulated exposures were comparable across body weights (AUC₀₋tau: 367, 377, 404, and 417 hr•ng/mL for 10–20 kg, 20–40 kg, 40–60 kg, and >60 kg groups, respectively). Dose reduction was required in 41.5% of virtual patients; most occurred within the first 3 months.
Conclusions: The revised regimen ensures consistent exposures across weight groups while simplifying dosing and lowering the risk of thrombocytopenia-related reductions. This aligns with EPIDYS, wherein >95% of patients completed the study without clinical manifestations after dose reductions to manage platelet decreases.