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

Purpose: Thrombopoietin is being investigated as a therapeutic agent for platelet recovery following myelosuppressive therapy. Little information is available, however, on the optimal dose of this drug or the timing of its administration. 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 recombinant 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 myeloablation model, mice were exposed to 900 to 950 rad of whole-body irradiation 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 received 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 rate of 50% compared to 0% for mice that had received recombinant murine thrombopoietin 2 h prior to whole-body irradiation. When the whole-body irradiation 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 thrombopoietin 2 h prior to whole-body irradiation. Dosing with recombinant murine thrombopoietin 7 days prior to whole-body irradiation resulted in a mortality rate greater than or equal to that of control mice. Conclusions: These data suggest that pretreatment with thrombopoietin can dramatically affect 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.