A Single Intravenous Dose of Murine Megakaryocyte Growth and Development Factor Potently Stimulates Platelet Production, Challenging the Necessity for Daily Administration

Abstract

The thrombopoietic efficacy of recombinant forms of c-mplligand is being actively investigated in preclinical studies using daily dosing schedules. However, a comprehensive kinetic study of the thrombopoietic response to a single injection of recombinant c-mpl ligand has not been performed. Here, we present the results of a detailed kinetic analysis of the platelet response to a single intravenous administration of pegylated recombinant murine megakaryocyte growth and development factor (PEG-rmMGDF) in mice. In addition, we compare the efficacy of single versus daily dosing in stimulating platelet production. A single intravenous injection of PEG-rmMGDF produced a marked and dose-dependent elevation in platelet number and a moderate increase in mean platelet volume (MPV). After administration of 25 or 250 μg/kg of PEG-rmMGDF, platelet number was first increased on day 3 and peaked at 2.7-fold (25 μg/kg) and 5.7-fold of normal (250 μg/kg) on day 5. Thereafter, platelet number declined and returned to baseline by days 9 and 14, with the 25 and 250 μg/kg doses, respectively. MPV began to increase on day 2 after PEG-rmMGDF, reaching maximum values of 1.2-fold (25 μg/kg) and 1.5-fold of normal (250 μg/kg) on day 4. Subsequently, MPV declined and was downregulated on days 6 to 7 (25 μg/kg) and day 8 (250 μg/kg). Based on these results, we evaluated the platelet response to PEG-rmMGDF administered intravenously as a single dose versus daily for 5 days. A single administration of 100 μg/kg produced a higher platelet number on day 5 than daily administration of 100 or 20 μg/kg for 5 days. However, the thrombocytosis was less sustained after single versus daily dosing. The smaller platelet number increase on day 5 after daily dosing reflected the production of larger platelets, rather than suppression of thrombopoiesis. Our results indicate that PEG-rmMGDF administered as a single intravenous dose potently stimulates platelet production in mice, challenging the need for its daily administration. Adoption of an intermittent administration schedule of this cytokine could be more efficacious and is merited in future clinical trials.