Semi-physiological pharmacokinetic-pharmacodynamic (PK/PD) models for troxacitabine-induced neutropenia and thrombocytopenia

Abstract

13002 Background: Neutropenia and thrombocytopenia are the dose-limiting toxicities of troxacitabine in Phase 1 studies. The present study’s aim was to develop a novel semi-physiological PK/PD model that can simultaneously describe the time course of the absolute neutrophil and platelet count changes in cancer patients receiving troxacitabine. Methods: The mixed-effect modeling was performed using the Monte-Carlo Parametric Expectation Maximization algorithm implemented in SADAPT program. The analysis was based on PK/PD data from 31 subjects who received troxacitabine/cisplatin combination every 28 days at five different dose levels (4.8/50, 4.8/75, 6.4/50, 6.4/75, 8.0/75 mg/m2). The PD model consisted of 1) a troxicatabine-sensitive uncommitted progenitor cell compartment, which differentiates into committed neutrophil and platelet progenitor cells that are also sensitive to the troxacitabine, and 2) transit compartments for neutrophils and platelets that represent maturation stages in bone marrow. To capture the rebound phenomena and maintain the hemostasis, the model included a feedback mechanism for both neutrophils and platelets. The troxacitabine concentrationtion-time profiles affected the proliferation of sensitive progenitor cells through an inhibitory sigmoidal Emax model. A three-compartment linear pharmacokinetic model was developed to describe the troxaicibatine concentration-time profile. Results: The PD model described the time-course of troxacitabine- induced neutrophil and platelet cytopenias and accounted for the large observed inter-patient variability. The model predicted that neutrophil progenitor cells were more sensitive to troxacitabine therapy compared to platelet progenitor cells. Furthermore, the model suggested that the troxacitabine-induced neutropenia and thrombocytopenia are reversible and non-cumulative events. Conclusions: This novel model can describe both the intensity and duration of troxacitabine-induced thrombocytopenia and neutropenia rather than simply considering the nadir values. It may be valuable for selecting treatment regimens that minimize troxacitabine’s dose-limiting hematological toxicities. No significant financial relationships to disclose.