Semi-mechanistic KPD model for haematological toxicity in breast cancer patients receiving high dose of chemotherapy
Ramón-López A. (1), Nalda-Molina R. (1), Valenzuela B. (1), Pérez Ruixo J.J.(1), Jiménez Torres N.V.(2),
(1) Pharmacy and Pharmaceutics Division, Department of Engineering, Faculty of Pharmacy, Miguel Hernández University, Spain. (2) Pharmacy Department, Hospital Universitario Dr. Peset, Valencia, Spain
High dose chemotherapy (HDC) and peripheral blood stem-cells transplantation (PBSCT) is a therapeutic strategy, which seems to improve disease free survival and overall survival in high risk breast cancer patients. Hematological toxicity is the major cause of the complications after HDC + PBSCT. The purpose of the current analysis is to develop a semi-mechanistic KPD model that describes the time course of the absolute neutrophil count (ANC) in breast cancer subjects receiving HDC and PBSCT.
Forty-one patients with diagnosis of high risk breast cancer and treated intravenously with STAMP-V protocol (6 mg/m2 cyclophosphamide, 0.5 mg/m2 thiotepa and 0.8 mg/m2 carboplatin) were included in this study. PBSCT was performed 3 days after the end of the chemotherapy. Patients were randomised to received G-CSF 1 or 5 days after the PBSCT. Daily measurements of ANC were available for the analysis.
The model was based on a drug-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound phenomena and the effect of the granulocyte colony-stimulating factor (G-CSF) and the CD34+ cell count reinfused, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (ANC0), mean transit time in bone marrow (MTT), and a feedback parameter. Due to the absence of pharmacokinetic data, a ‘kinetics of drug action’ was used to quantify the reduction of the proliferation rate and/or the increase in the killing rate of the progenitor cells. Model evaluation was examined using goodness of fit plots, relative error measurements, and posterior predictive checks. Computer simulations were undertaken to evaluate the neutropenia schedule dependency.
The model developed was suitable to describe the extent and the duration of the grade 4 neutropenia in breast cancer patients receiving HDC + PBSCT.
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