title: Effects of formulation and route of administration on the systemic availability of Ex-RAD®, a new radioprotectant, in preclinical species.
abstract: ON 01210.Na (Ex-RAD®) is a novel small molecule under development by Onconova Therapeutics, Inc. as a radiation protection agent. The purpose of this investigation was to evaluate the effect of various formulation approaches on the systemic exposure of ON 01210.Na. In vitro experiments were used to characterize the plasma binding and metabolic stability of ON 01210.Na using hepatocytes from several animal species (mouse, rat, rabbit, dog, monkey and human). In vivo studies were performed in rats, rabbits, dogs and monkeys, and involved several routes of administration (intravenous, subcutaneous, oral). Plasma protein binding was high across species (>83%), and the rate of ON 01210.Na metabolism was highest in rat and mouse hepatocytes. After intravenous administration, ON 01210.Na demonstrated biphasic elimination from the plasma. Systemic exposure parameters (Cmax, AUC) were dose-proportional up to 100 mg/kg. Following subcutaneous dosing, ON 01210.Na showed relatively low bioavailability upon administration of the suspension formulation. Developing a solution formulation significantly increased the bioavailability of the drug. This solution formulation demonstrated significant oral bioavailability in rabbit (70%) and monkey (30%). The findings from these preclinical studies provide an overview of the systemic disposition of ON 01210.Na, aiding in the development of optimal formulations and routes of administration for pivotal animal efficacy and clinical safety studies. A solution formulation of ON 01210.Na for s.c. administration is being developed, in addition to an oral dosage form for potential use of the compound as a radioprotectant and a radiation-mitigating agent in wider military and civilian populations.
authors.affiliation: Division of Pharmaceutical Sciences, Long Island University, Brooklyn, NY 11201, USA.
authors.forename: Amy W
authors.initials: AW
authors.lastname: Chun
authors.forename: Robert E
authors.initials: RE
authors.lastname: Freshwater
authors.forename: David R
authors.initials: DR
authors.lastname: Taft
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gillum
authors.forename: Manoj
authors.initials: M
authors.lastname: Maniar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011485:Protein Binding; D011817:Rabbits; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: C520364:(E)-4-carboxystyryl-4-chlorobenzylsulfone, sodium salt; D001798:Blood Proteins; D011837:Radiation-Protective Agents; D013449:Sulfonamides