A semi-physiological-based pharmacokinetic/pharmacodynamic model to describe the effects of topotecan on b-lymphocyte lineage cells.

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.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Vélez de Mendizábal N,Martínez-Forero I,Garrido MJ,Bandrés E,García-Foncillas J,Segura C,Trocóniz IF

doi

10.1007/s11095-009-0025-x

subject

Has Abstract

pub_date

2010-03-01 00:00:00

pages

431-41

issue

3

eissn

0724-8741

issn

1573-904X

journal_volume

27

pub_type

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