Open AccessA physiological model of granulopoiesis to predict clinical drug induced neutropenia from in vitro bone marrow studies: with application to a cell cycle inhibitor
Author(s) -
Wenbo Chen,
Britton Boras,
Tae Sung,
Yanke Yu,
Jenny Zheng,
Diane Wang,
Wenyue Hu,
Mary E. Spilker,
David Z. D’Argenio
Publication year - 2020
Publication title -
journal of pharmacokinetics and pharmacodynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.827
H-Index - 60
eISSN - 1573-8744
pISSN - 1567-567X
DOI - 10.1007/s10928-020-09680-6
Subject(s) - granulopoiesis , palbociclib , neutropenia , pharmacology , medicine , bone marrow , filgrastim , granulocyte , granulocyte colony stimulating factor , immunology , progenitor cell , biology , chemotherapy , stem cell , breast cancer , cancer , microbiology and biotechnology , metastatic breast cancer
Neutropenia is one of the most common dose-limiting toxocities associated with anticancer drug therapy. The ability to predict the probability and severity of neutropenia based on in vitro studies of drugs in early drug development will aid in advancing safe and efficacious compounds to human testing. Toward this end, a physiological model of granulopoiesis and its regulation is presented that includes the bone marrow progenitor cell cycle, allowing for a mechanistic representation of the action of relevant anticancer drugs based on in vitro studies. Model development used data from previously reported tracer kinetic studies of granulocyte disposition in healthy humans to characterize the dynamics of neutrophil margination in the presence of endogenous granulocyte-colony stimulating factor (G-CSF). In addition, previously published data from healthy volunteers following pegfilgrastim and filgrastim were used to quantify the regulatory effects of support G-CSF therapies on granulopoiesis. The model was evaluated for the cell cycle inhibitor palbociclib, using an in vitro system of human bone marrow mononuclear cells to quantify the action of palbociclib on proliferating progenitor cells, including its inhibitory effect on G1 to S phase transition. The in vitro results were incorporated into the physiological model of granulopoiesis and used to predict the time course of absolute neutrophil count (ANC) and the incidence of neutropenia observed in three previously reported clinical trials of palbociclib. The model was able to predict grade 3 and 4 neutropenia due to palbociclib treatment with 86% accuracy based on in vitro data.