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A Semi-physiological-Based Pharmacokinetic/Pharmacodynamic Model to Describe the Effects of Topotecan on B-Lymphocyte Lineage Cells

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Abstract

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.

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Authors and Affiliations

  1. Neuroimmunology Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain

    Nieves Vélez de Mendizábal

  2. Department of Computational Sciences and Artificial Intelligence, University of the Basque Country, San Sebastian, Spain

    Nieves Vélez de Mendizábal

  3. Gene Therapy Unit, Center for Applied Medical Research, University of Navarra, Pamplona, Spain

    Iván Martínez-Forero

  4. Department of Physics and Applied Mathematics, University of Navarra, Pamplona, Spain

    Iván Martínez-Forero

  5. Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Navarra, Pamplona, 31080, Spain

    María J. Garrido, Cristina Segura & Iñaki F. Trocóniz

  6. Laboratory of Pharmacogenomics, Cancer Research Program (Center for Applied Medical Research), University of Navarra, Pamplona, Spain

    Eva Bandrés & Jesús García-Foncillas

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  1. Nieves Vélez de Mendizábal
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  2. Iván Martínez-Forero
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  3. María J. Garrido
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  4. Eva Bandrés
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  6. Cristina Segura
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  7. Iñaki F. Trocóniz
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Corresponding author

Correspondence to Iñaki F. Trocóniz.

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Vélez de Mendizábal, N., Martínez-Forero, I., Garrido, M.J. et al. A Semi-physiological-Based Pharmacokinetic/Pharmacodynamic Model to Describe the Effects of Topotecan on B-Lymphocyte Lineage Cells. Pharm Res 27, 431–441 (2010). https://doi.org/10.1007/s11095-009-0025-x

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  • DOI: https://doi.org/10.1007/s11095-009-0025-x

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