PURPOSE: 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.
PURPOSE: 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: Lillian Sung; Paul C Nathan; Shabbir M H Alibhai; George A Tomlinson; Joseph Beyene Journal: Ann Intern Med Date: 2007-09-18 Impact factor: 25.391
Authors: Cristina Segura; Eva Bandrés; Iñaki F Trocóniz; Jesús García-Foncillas; Onintza Sayar; Carmen Dios-Vieítez; Maria Jesús Renedo; María J Garrido Journal: Pharm Res Date: 2004-04 Impact factor: 4.200