Population pharmacokinetic–pharmacodynamic analysis of givinostat

Abstract

Background: Givinostat (ITF2357), an oral, synthetic histone deacetylase inhibitor, significantly improved all histological muscle biopsy parameters in a Phase II study in boys with Duchenne muscular dystrophy (DMD). Research Design and Methods: A population pharmacokinetic (PK) model, including seven clinical studies, was developed to explore the effect of covariates on givinostat PK. The final model was qualified to simulate pediatric dosing recommendations. A PK/pharmacodynamic (PD) model was developed to simulate the link between givinostat plasma concentration and platelet time course in 10–70-kg children following 6 months of givinostat 20–70 mg twice daily. Results: A two-compartment model, with first-order input with lag and first-order elimination from the central compartment, described givinostat PK, demonstrating increasing apparent clearance with increasing body weight. The PK/PD model well-described platelet count time course. Weight-based dosing (arithmetic mean systemic exposure of 554–641 ng·h/mL) produced an average platelet count decrease from baseline of 45% with maximum decrease within 28 days. After 1 week and 6 months, ~1% and ~14–15% of patients, respectively, had a platelet count <75 × 109/L. Conclusions: Based on these data, givinostat dosing will be body weight adjusted and include monitoring of platelet counts to support efficacy and safety in a Phase III DMD study.