Dose schedule of recombinant murine thrombopoietin prior to myelosuppressive and myeloablative therapy in mice

Purpose: Thrombopoietin is being investigated as a therapeutic agent for pl atelet recovery following myelosuppressive therapy. Little information is a vailable, however, on the optimal dose of this drug or the timing of its ad ministration. To develop these data, a series of studies were conducted to examine the effects that time of dosing has on the efficacy and safety of r ecombinant full-length murine thrombopoietin in murine myelosuppression and murine myeloablation models. Methods: For the myelosuppression model, mice were exposed to 500 rad whole-body irradiation in a cesium irradiator and received an intraperitoneal dose of 1.2 mg carboplatin at time 0. For the m yeloablation model, mice were exposed to 900 to 950 rad of whole-body irrad iation at time 0. Results: Significant increases in the number of platelets and red and white blood cells were observed by day 10 in mice that had rec eived a single intravenous bolus dose of recombinant murine thrombopoietin from 2 h before until 4 h after myelosuppressive therapy compared to those had received myelosuppressive therapy alone. In the myeloablation studies, mice treated with 900 rad of whole-body irradiation alone had a mortality r ate of 50% compared to 0% for mice that had received recombinant murine thr ombopoietin 2 h prior to whole-body irradiation. When the whole-body irradi ation dose was increased to 950 rad, the mortality rate of the control mice was 83% compared to 25% for mice that had received recombinant murine thro mbopoietin 2 h prior to whole-body irradiation. Dosing with recombinant mur ine thrombopoietin 7 days prior to whole-body irradiation resulted in a mor tality rate greater than or equal to that of control mice. Conclusions: The se data suggest that pretreatment with thrombopoietin can dramatically affe ct recovery from myelosuppressive and myeloablative therapy. Therefore, the timing of thrombopoietin administration in relation to the therapy may be critical to the drug's safety and efficacy.