Journal Article

Application of Hematological Toxicity Modeling in Clinical Development of Abexinostat (S-78454, PCI-24781), A New Histone Deacetylase Inhibitor

Kloos, Ioana, Robert, Renata, Jacquet-Bescond, Anne, Chatelut, Etienne, Depil, Stéphane, Chalret du Rieu, Quentin, Fouliard, Sylvain, Chenel, Marylore

2013

Overview

Purpose A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the thrombocytopenia (dose-limiting toxicity) of abexinostat, a new histone deacetylase inhibitor. An optimal administration schedule of the drug was determined using a simulation-based approach. Methods Early PK and PK/PD data were analysed using a sequential population modeling approach (NONMEM 7), allowing for the description of a PK profile and platelet-count decrease after abexinostat administration with various administration schedules. Simulations of platelet count with several administration schedules over 3-week treatment cycles (ASC) and over a day (ASD) were computed to define the optimal schedule that limits the depth of thrombocytopenia. Results An intermediate PK/PD model accurately described the data. The administration of abexinostat during the first 4 days of each week in a 3-week cycle resulted in fewer adverse events (with no influence of ASD on platelet count profiles), and corresponded to the optimal treatment schedule. This administration schedule was clinically evaluated in a phase I clinical trial and allowed for the definition of a new maximum tolerated dose (MTD), leading to a nearly 30% higher dose-intensity than that of another previously tested schedule. Lastly, a final model was built using all of the available data. Conclusions The final model, characterizing the dose-effect and the dose-toxicity relationships, provides a useful modeling tool for clinical drug development.

• Publisher: Springer US,Springer,Springer Nature B.V
• Subject: Benzofurans - administration & dosage / Benzofurans - pharmacokinetics / Benzofurans - pharmacology / Benzofurans - toxicity / Biochemistry / Biological and medical sciences / Biomedical and Life Sciences / Biomedical Engineering and Bioengineering / Biomedicine / Clinical Trials, Phase I as Topic / Computer Simulation / Dose-Response Relationship, Drug / Drug Administration Schedule / Drug delivery systems / Hematologic and hematopoietic diseases / Histone Deacetylase Inhibitors - administration & dosage / Histone Deacetylase Inhibitors - pharmacokinetics / Histone Deacetylase Inhibitors - pharmacology / Histone Deacetylase Inhibitors - toxicity / Humans / Hydroxamic Acids - administration & dosage / Hydroxamic Acids - pharmacokinetics / Hydroxamic Acids - pharmacology / Hydroxamic Acids - toxicity / Kinetics / Medical Law / Medical sciences / Models, Biological / Pharmacology / Pharmacology. Drug treatments / Pharmacology/Toxicology / Pharmacy / Platelet Count / Platelet diseases and coagulopathies / Research Paper / Simulation / Thrombocytopenia - blood / Thrombocytopenia - chemically induced