Pharmacodynamic model for chemoradiotherapy-induced thrombocytopenia in mice.
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.
Department of Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
Wojciech
W
Krzyzanski
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91360, USA.
Juan Jose
JJ
Perez-Ruixo
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91360, USA. jharrold@amgen.com.
John
J
Harrold
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects*; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity*; D059248:Chemoradiotherapy / Q000009:adverse effects*; D003198:Computer Simulation; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D051379:Mice; D008954:Models, Biological; D015233:Models, Statistical; D010976:Platelet Count; D011829:Radiation Dosage; D011832:Radiation Injuries / Q000097:blood / Q000139:chemically induced*; D053628:Receptors, Thrombopoietin / Q000097:blood; D018570:Risk Assessment; D013921:Thrombocytopenia / Q000097:blood / Q000139:chemically induced*; D034061:Thrombopoiesis / Q000187:drug effects / Q000528:radiation effects; D013926:Thrombopoietin / Q000097:blood; D013997:Time Factors; D014916:Whole-Body Irradiation / Q000009:adverse effects*
D000970:Antineoplastic Agents; D015415:Biomarkers; C481270:Mpl protein, mouse; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin; D016190:Carboplatin
Chemoradiation; Receptor-mediated disposition; Thrombocytopenia; Thrombopoietin