Population pharmacokinetic-pharmacodynamic analysis of givinostat.

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Fiorentini F, Germani M, Del Bene F, Pellizzoni C, Cazzaniga S, Rocchetti M, Bettica P

Population pharmacokinetic-pharmacodynamic analysis of givinostat.

Expert Opin Drug Metab Toxicol. 2023 Apr;19(4):229-238. doi: 10.1080/17425255.2023.2219839. Epub 2023 Jun 12.

PubMed ID
37306105 [ View in PubMed
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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 x 10(9)/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.

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