title: A semi-physiological-based pharmacokinetic/pharmacodynamic model to describe the effects of topotecan on b-lymphocyte lineage cells.
abstract: OBJECTIVE
  To develop a semi-physiological-based model describing simultaneously the time course of immature and mature B-lymphocytes after topotecan (TPT) administration to tumor-bearing rats.
  
  
  METHODS
  Twenty-four tumor-bearing BDIX male rats received a single 6 mg/kg intra-peritoneal dose of TPT or saline. Mature and immature B-cell levels were measured every two days during three weeks and showed a very different temporal pattern. Both B-cell populations declined rapidly, reaching the nadir at 3-4 days after TPT administration; however, mature cells returned to baseline at day 8, while immature B-cells stayed at nadir until day 9 instead. Data were modeled using the population approach with NONMEM VI.
  
  
  RESULTS
  The model developed maintains the proliferation, maturation and degradation elements of previous published models for myelosuppresion. In order to describe the rapid recovery of mature cells, it includes a peripheral compartment providing a constant supply of mature cells to the bloodstream.
  
  
  CONCLUSIONS
  The major contribution of the model is its new structure and the dynamical consequences, demonstrating an independent behavior between mature and immature B-cells during recovery. The final model could represent a good basis for the optimization of cytotoxic drugs oriented to attain a maximum antitumor efficacy while minimizing hematological toxicity.
authors.affiliation: Neuroimmunology Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Nieves
authors.initials: N
authors.lastname: Vélez de Mendizábal
authors.forename: Iván
authors.initials: I
authors.lastname: Martínez-Forero
authors.forename: María J
authors.initials: MJ
authors.lastname: Garrido
authors.forename: Eva
authors.initials: E
authors.lastname: Bandrés
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Foncillas
authors.forename: Cristina
authors.initials: C
authors.lastname: Segura
authors.forename: Iñaki F
authors.initials: IF
authors.lastname: Trocóniz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008954:Models, Biological; D051381:Rats; D019772:Topotecan / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan