title: Pharmacokinetic/Pharmacodynamic modeling of abexinostat-induced thrombocytopenia across different patient populations: application for the determination of the maximum tolerated doses in both lymphoma and solid tumour patients.
abstract: BACKGROUND
  In the clinical development of oncology drugs, the recommended dose is usually determined using a 3 + 3 dose-escalation study design. However, this phase I design does not always adequately describe dose-toxicity relationships.
  
  
  METHODS
  125 patients, with either solid tumours or lymphoma, were included in the study and 1217 platelet counts were available over three treatment cycles. The data was used to build a population pharmacokinetic/pharmacodynamic (PKPD) model using a sequential modeling approach. Model-derived Recommended Doses (MDRD) of abexinostat (a Histone Deacetylase Inhibitor) were determined from simulations of different administration schedules, and the higher bound for the probability of reaching these MDRD with a 3 + 3 design were obtained.
  
  
  RESULTS
  The PKPD model developed adequately described platelet kinetics in both patient populations with the inclusion of two platelet baseline counts and a disease progression component for patients with lymphoma. Simulation results demonstrated that abexinostat administration during the first 4 days of each week in a 3-week cycle led to a higher MDRD compared to the other administration schedules tested, with a maximum probability of 40 % of reaching these MDRDs using a 3 + 3 design.
  
  
  CONCLUSIONS
  The PKPD model was able to predict thrombocytopenia following abexinostat administration in both patient populations. A model-based approach to determine the recommended dose in phase I trials is preferable due to the imprecision of the 3 + 3 design.
authors.affiliation: Clinical Pharmacokinetics Department, Institut de Recherches Internationales Servier, Suresnes, France.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Chalret du Rieu
authors.forename: Sylvain
authors.initials: S
authors.lastname: Fouliard
authors.forename: Mélanie
authors.initials: M
authors.lastname: White-Koning
authors.forename: Ioana
authors.initials: I
authors.lastname: Kloos
authors.forename: Etienne
authors.initials: E
authors.lastname: Chatelut
authors.forename: Marylore
authors.initials: M
authors.lastname: Chenel
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001572:Benzofurans / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D020714:Maximum Tolerated Dose; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C512352:abexinostat