Journal
INTERNATIONAL JOURNAL OF TOXICOLOGY
Volume 32, Issue 2, Pages 100-112Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1091581813482336
Keywords
thrombopoietin receptor agonist; single-dose toxicity; drug development; megakaryopoiesis; nonclinical safety evaluation; platelets
Categories
Funding
- National Institute of Allergy and Infectious Diseases (NIAID)
Ask authors/readers for more resources
ALXN4100TPO, a thrombopoietin (TPO) receptor agonist, increases platelets, abrogates radiation-induced thrombocytopenia and affords significant survival benefit to lethally irradiated mice. This preliminary nonclinical safety study assessed effects of a single subcutaneous (sc) administration of ALXN4100TPO in CD2F1 mice randomized into naive, control antibody (ALXN4200, 100 mg/kg), low(1 mg/kg), medium (10 mg/kg), or high (100 mg/kg) ALXN4100TPO doses. End points included clinical observations, body weight changes, hematology, histopathology, pharmacokinetics, pharmacodynamics by measuring platelet counts, and endogenous TPO (eTPO) levels. Salient findings were prominent increase in platelet counts and end cells of myeloid and lymphoid lineages; elevated megakaryopoiesis in bone marrow; and extramedullary hematopoiesis in spleen and liver. Serum ALXN4100TPO levels were maximum 24 hours after administration, with a half-life of 13 days. Endogenous TPO levels were elevated in 10 and 100 mg/kg ALXN4100TPO-treated groups. In conclusion, ALXN4100TPO (1-100 mg/kg, sc) treatment in CD2F1 mice resulted in profound pharmacological changes in the hematopoietic tissue; however, no life-threatening adverse events were observed.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available