title: Application of hematological toxicity modeling in clinical development of abexinostat (S-78454, PCI-24781), a new histone deacetylase inhibitor.
abstract: OBJECTIVE
  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.
authors.affiliation: Clinical Pharmacokinetics Department, Institut de Recherches Internationales Servier, 50 rue Carnot, 92284, Suresnes Cedex, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Chalret du Rieu
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fouliard
authors.forename: Anne
authors.initials: A
authors.lastname: Jacquet-Bescond
authors.forename: Renata
authors.initials: R
authors.lastname: Robert
authors.forename: Ioana
authors.initials: I
authors.lastname: Kloos
authors.forename: Stéphane
authors.initials: S
authors.lastname: Depil
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Marylore
authors.initials: M
authors.lastname: Chenel
mesh_terms: D001572:Benzofurans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D017321:Clinical Trials, Phase I as Topic; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D008954:Models, Biological; D010976:Platelet Count; D013921:Thrombocytopenia / Q000097:blood* / Q000139:chemically induced
chemical_list: D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C512352:abexinostat