A semi-physiological-based pharmacokinetic/pharmacodynamic model to describe the effects of topotecan on b-lymphocyte lineage cells.
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.
Vélez de Mendizábal
Nieves
N
Neuroimmunology Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
Martínez-Forero
Iván
I
Garrido
María J
MJ
Bandrés
Eva
E
García-Foncillas
Jesús
J
Segura
Cristina
C
Trocóniz
Iñaki F
IF
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*
D000970:Antineoplastic Agents; D019772:Topotecan