title: Comparison of different semi-mechanistic models for chemotherapy-related neutropenia: application to BI 2536 a Plk-1 inhibitor.
abstract: OBJECTIVE
  The aim of this investigation was to compare the performance of a commonly used semi-mechanistic model for drug-related neutropenia with other semi-mechanistic models published in the literature.
  
  
  METHODS
  After their implementation in NONMEM VI, five semi-mechanistic models were assessed using the pharmacokinetic and absolute neutrophil count data obtained from 95 patients with non-small cell lung cancer receiving either 200 mg on day 1 or 50 or 60 mg on days 1, 2 and 3 of a 21-day treatment course with the new Plk-1 inhibitor BI 2536. The model performance was compared by means of predictive (visual and numerical) checks, precision in the parameter estimates and objective function-based measures. Details of model parameterization, model stability and run times are also provided.
  
  
  RESULTS
  The time course of the drug plasma concentrations was described by a three compartment model with a first-order elimination rate. With respect to neutropenia, all models were successfully implemented in NONMEM and provided reasonable fits for the median (although not all models described all percentiles of the data well), and in general precise parameter estimates.
  
  
  CONCLUSIONS
  In the current evaluation performed in a single drug, none of the models showed superior performance compared to the most commonly used model first described by Friberg et al. (J Clin Oncol 20:4713-4721, 2002).
authors.affiliation: Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, 31080 Pamplona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Soto
authors.forename: Alexander
authors.initials: A
authors.lastname: Staab
authors.forename: Christiane
authors.initials: C
authors.lastname: Doege
authors.forename: Matthias
authors.initials: M
authors.lastname: Freiwald
authors.forename: Gerd
authors.initials: G
authors.lastname: Munzert
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000009:adverse effects*; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011621:Pteridines; D000097869:Polo-Like Kinase 1; C518477:BI 2536