Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients

• Published in: Pharmaceutical research 2009-08, Vol.26 (8), p.1952-1962
• Main Authors: Ramon-Lopez, Amelia, Nalda-Molina, Ricardo, Valenzuela, Belen, Perez-Ruixo, Juan Jose
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Breast cancer; Breast Neoplasms - blood; Breast Neoplasms - complications; Breast Neoplasms - drug therapy; Chemotherapy; Dose-Response Relationship, Drug; Female; General pharmacology; Humans; Kinetics; Medical Law; Medical sciences; Middle Aged; Models, Biological; Neutropenia - chemically induced; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Research Paper; Stem cells
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-009-9910-6

Purpose 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 (α). Results The typical of the ANC at baseline (Circ ₀ ), mean transit time (MTT), feedback parameter (γ), k in 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. Conclusion 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.