Preliminary Nonclinical Toxicity, Pharmacokinetics, and Pharmacodynamics of ALXN4100TPO, a Thrombopoietin Receptor Agonist, in CD2F1 Mice

Author:

Satyamitra Merriline1,Lombardini Eric1,Peng Tao2,Devore Denise2,Graves John1,Mullaney Conor1,Ney Patrick1,Srinivasan Venkataraman1

Affiliation:

1. Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

2. Alexion Pharmaceuticals, Inc, Cheshire, CT, USA

Abstract

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 naïve, 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.

Publisher

SAGE Publications

Subject

Toxicology

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