1. Application of Hematological Toxicity Modeling in Clinical Development of Abexinostat (S-78454, PCI-24781), A New Histone Deacetylase Inhibitor.
- Author
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Chalret du Rieu, Quentin, Fouliard, Sylvain, Jacquet-Bescond, Anne, Robert, Renata, Kloos, Ioana, Depil, Stéphane, Chatelut, Etienne, and Chenel, Marylore
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THROMBOCYTOPENIA treatment , *HEMATOLOGIC malignancies , *HISTONE deacetylase inhibitors , *PHARMACOKINETICS , *BLOOD platelets , *ADVERSE health care events - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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