Objective: The objective of this study was to evaluate the tolerability, pharmacodynamics, and pharmacokinetics of AMG 531, a novel thrombopoietin receptor ligand, after a single intravenous or subcutaneous injection in healthy subjects.
Methods: This was a first-in-human randomized, double-blind, placebo-controlled study with 48 subjects. Six subjects in each cohort were sequentially randomized in a 2:1 ratio to receive a single injection of AMG 531 or placebo. The dose ranges investigated were 0.3 to 10.0 microg/kg and 0.1 to 2.0 microg/kg via the intravenous and subcutaneous dosing routes, respectively. The pharmacodynamic response of AMG 531 was measured as the elevation in platelet counts. AMG 531 serum levels were determined by use of a validated enzyme-linked immunosorbent assay.
Results: Single intravenous or subcutaneous administration of AMG 531 induced a dose-dependent increase in platelet count in healthy subjects, with peak platelet count being achieved on days 12 to 16. The highest intravenous dose, 10.0 microg/kg, caused a nearly 6-fold increase in platelet count. The maximum increase for this cohort occurred on day 15, and the mean platelet count was 1380 x 10(9)/L (range, 923-1790 x 10(9)/L). Of 8 subjects receiving the 2.0-microg/kg subcutaneous dose, 6 had peak platelet levels that were double the baseline value. Platelet count was elevated to a similar extent after single intravenous or subcutaneous administration of AMG 531 at the same dose level (1.0 microg/kg), even though the subcutaneous serum levels were barely detectable. Platelet counts were close to the baseline value by day 28. After a single intravenous administration, the pharmacokinetics of AMG 531 was nonlinear in the 0.3- to 10.0-microg/kg dose range. Most AMG 531 serum levels fell below the assay's lower quantitation limit of 18 pg/mL after a single subcutaneous dose. There were no serious or life-threatening adverse events reported in this study. The most frequently reported events were mild to moderate headache and sore throat.
Conclusion: AMG 531 was well tolerated in this study and was effective at raising platelet counts in healthy volunteers after single intravenous or subcutaneous administration.