Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients
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- Ramon-Lopez, A., Nalda-Molina, R., Valenzuela, B. et al. Pharm Res (2009) 26: 1952. doi:10.1007/s11095-009-9910-6
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To describe the absolute neutrophil counts (ANC) profile in breast cancer patients receiving high-dose of chemotherapy and peripheral blood stem-cells (PBSC) transplantation.
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, kin, 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 (α).
The typical of the ANC at baseline (Circ0), mean transit time (MTT), feedback parameter (γ), kin and α were estimated to be 5,610·106/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.
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.