title: Population pharmacokinetic-pharmacodynamic modelling and simulation of neutropenia induced by TP300, a novel topoisomerase I inhibitor.
abstract: OBJECTIVE
  TP300 is a novel topoisomerase I inhibitor with neutropenia as a significant toxicity. We developed and evaluated a pharmacokinetic-pharmacodynamic (PK-PD) model, using data from Phase I and II trials to predict neutrophil decrease in patients treated with TP300.
  
  
  METHODS
  Plasma drug concentrations of TP300, its active form TP3076 and active metabolite TP3011 and absolute neutrophil counts (ANCs) from a Phase I trial were analysed as a training dataset. A two-plus-two-compartment model was applied to the pharmacokinetics of TP3076 and TP3011. A semi-mechanistic model was used to describe the PK-PD relationship between the plasma concentration of TP3076 and TP3011, and changes in ANC.
  
  
  RESULTS
  The model fitted well to plasma concentrations of TP3076 and TP3011. Model appropriateness was confirmed in a Phase II trial validation dataset. Body weight and liver biochemistry values were identified as covariates. A semi-mechanistic PK-PD model was applied and the longitudinal decrease in ANC was simulated. Neutrophil counts reached their nadir approximately 2 weeks after administration of TP300, and the proportion of subjects affected increased with dose.
  
  
  CONCLUSIONS
  This PK-PD model to predict neutropenia following treatment with TP300 fitted well the decrease in ANC with total concentration of TP3076 and TP3011.
authors.affiliation: Research Planning Department, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Saito
authors.forename: Satofumi
authors.initials: S
authors.lastname: Iida
authors.forename: Masaichi
authors.initials: M
authors.lastname: Abe
authors.forename: Keith
authors.initials: K
authors.lastname: Jones
authors.forename: Takehiko
authors.initials: T
authors.lastname: Kawanishi
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
mesh_terms: D001711:Biotransformation; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003198:Computer Simulation; D004151:Dipeptides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D009010:Monte Carlo Method; D009503:Neutropenia / Q000139:chemically induced*; D011237:Predictive Value of Tests; D012107:Research Design; D059004:Topoisomerase I Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D006576:Heterocyclic Compounds, 4 or More Rings; C558017:TP 300; D059004:Topoisomerase I Inhibitors
keywords: PK-PD; modelling; neutrophil counts; simulation; topoisomerase I inhibitor