Neuroimmunology Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Pharm Res. 2010 Mar;27(3):431-41. doi: 10.1007/s11095-009-0025-x. Epub 2010 Jan 26.
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.
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.
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.
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.
建立一个半生理基于模型，描述拓扑替康（TPT）给药后荷瘤大鼠未成熟和成熟 B 淋巴细胞的时间过程。
24 只荷瘤 BDIX 雄性大鼠接受单次 6mg/kg 腹腔 TPT 或生理盐水剂量。在三周内每两天测量一次成熟和未成熟 B 细胞水平，表现出非常不同的时间模式。两种 B 细胞群体迅速下降，在 TPT 给药后 3-4 天达到最低点；然而，成熟细胞在第 8 天恢复到基线，而未成熟 B 细胞则在第 9 天仍处于最低点。使用 NONMEM VI 进行群体分析对数据进行建模。
所开发的模型保留了先前发表的用于骨髓抑制的模型的增殖、成熟和降解元素。为了描述成熟细胞的快速恢复，它包括一个外周隔室，为血液提供成熟细胞的恒定供应。
该模型的主要贡献是其新结构和动力学后果，证明了在恢复过程中成熟和未成熟 B 细胞之间的独立行为。最终模型可以为优化细胞毒性药物提供良好的基础，旨在在最大程度地提高抗肿瘤疗效的同时最小化血液毒性。
