Semi-mechanistic model for neutropenia after high dose of chemotherapy in breast cancer patients.
OBJECTIVE
To describe the absolute neutrophil counts (ANC) profile in breast cancer patients receiving high-dose of chemotherapy and peripheral blood stem-cells (PBSC) transplantation.


METHODS
Data from 41 subjects receiving cyclophosphamide, thiotepa and carboplatin were used to develop the ANC model consisting of a drug-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments. PBSC were incorporated into the first transit compartment following a zero-order process, k(in), and the rebound effect was explained by a feedback mechanism. A 'kinetics of drug action' model was used to quantify the HDC effect on the progenitor cells according to a linear function, with a slope (alpha).


RESULTS
The typical of the ANC at baseline (Circ(0)), mean transit time (MTT), feedback parameter (gamma), k(in) and alpha were estimated to be 5,610 x 10(6)/L, 3.25 days, 0.145, 0.954 cell/kg/day and 2.50 h/U, respectively. rHuG-CSF shortens the MTT by 92% and increases the mitotic activity by 120%. Bootstrap analysis, visual predictive check and numerical predictive checks evidenced accurate prediction of the ANC nadir, time to ANC nadir and time to grade 4 neutropenia recovery.


CONCLUSIONS
The time course of neutropenia following high-dose of chemotherapy and PBSC transplantation was accurately predicted. Higher amount of CD34+ cells in the PBSC transplantation and earlier administration rHuG-CSF were associated with faster haematological recovery.
Ramon-Lopez
Amelia
A
Pharmacy and Pharmaceutics Division, Department of Engineering, Miguel Hernandez University, San Juan de Alicante, Alicante, Spain.
Nalda-Molina
Ricardo
R
Valenzuela
Belen
B
Perez-Ruixo
Juan Jose
JJ
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*
D000970:Antineoplastic Agents