title: Preliminary nonclinical toxicity, pharmacokinetics, and pharmacodynamics of ALXN4100TPO, a thrombopoietin receptor agonist, in CD2F1 mice.
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.
authors.affiliation: Armed Forces Radiobiology Research Institute (AFRRI), Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA. Merriline.Satyamitra.CTR@usuhs.edu
authors.forename: Merriline
authors.initials: M
authors.lastname: Satyamitra
authors.forename: Eric
authors.initials: E
authors.lastname: Lombardini
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.forename: Denise
authors.initials: D
authors.lastname: Devore
authors.forename: John
authors.initials: J
authors.lastname: Graves
authors.forename: Conor
authors.initials: C
authors.lastname: Mullaney
authors.forename: Patrick
authors.initials: P
authors.lastname: Ney
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Srinivasan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics* / Q000633:toxicity*; D061067:Antibodies, Monoclonal, Humanized; D001682:Biological Availability; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010976:Platelet Count; D053628:Receptors, Thrombopoietin / Q000819:agonists*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013921:Thrombocytopenia / Q000188:drug therapy / Q000473:pathology; D034061:Thrombopoiesis / Q000187:drug effects; D013926:Thrombopoietin / Q000493:pharmacokinetics* / Q000633:toxicity*
chemical_list: C559765:ALXN4100TPO; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin