Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice
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A mechanistic model describing the effects of chemotherapy and radiation on platelet counts and endogenous thrombopoietin (eTPO) in mice was developed. Thrombocytopenia was induced in mice by injection of carboplatin followed by the whole body irradiation on days 0, 28, and 56, with platelet and eTPO samples collected over 84 days. The pharmacodynamic model consisted of a series of aging compartments representing proliferating megakaryocyte precursors, megakaryocytes, and platelets with possible eTPO clearance through internalization. The cytotoxic effects of treatment were described by the kinetics of the effect (K-PD) model, and stimulation of platelet production by eTPO was considered to be driven by receptor occupancy. The proposed PD model adequately described the platelet counts and eTPO concentrations in mice by accounting for nadirs and peaks of platelet count, and rebounds in eTPO time course profiles. The estimates of model parameters were in good agreement with their physiological values reported in literature for mice with platelet lifespan of 4.3 days and 185 cMpl receptors per platelet. The predicted duration of the treatment effect was 0.82 h (approximately 5 carboplatin half-lives in mice). The data was not informative about the eTPO stimulatory effect as the nominal precursor production rate was sufficient to account for platelet response to treatment. The model quantified the inverse relationship between eTPO levels and platelet counts and offered an explanation of the tolerance effect observed in the eTPO data. The simulated rebound in free receptors levels correlated with rebounds in eTPO levels. The model suggests that the duration of the toxic effects is determined by the turnover of the proliferating cells in the bone marrow. This indicates that the lifespan of the target cells (megakaryocyte precursors, megakaryocytes and platelets) is a key determinant in the duration of both drug exposure and toxicity due to treatment. The model can be extended to account for pharmacokinetics of exogenous drugs and be applied to analysis of human data.
KeywordsChemoradiation Receptor-mediated disposition Thrombocytopenia Thrombopoietin
The authors would like to thank Graham Molineux, Ping Wei and Trish McElroy for conducting the experiments to generate the data used in this modeling exercise and Murad Melhem for critical review of the manuscript.
This study was sponsored by Amgen Inc., which was involved in the study design, data collection, analysis, interpretation, writing the manuscript, and the decision to submit the manuscript for publication.
Compliance with ethical standards
Potential conflicts of interest
The following authors are employees of and own stock in Amgen Inc.: Juan Jose Perez Ruixo and John Harrold. Wojciech Krzyzanski is a consultant for Amgen and received consultation fees for this work.
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