Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice

Abstract 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...
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research