Due to the short half-life and rapid clearance of the drug, administration of ON 01910.Na by continuous IV infusion is a likely treatment option for cancer patients.
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.
Introduction: ON 01910. Na is a novel targeted anti-cancer agent under clinical investigation in Phase I and Phase II trials. Preclinical studies indicate that the compound preferentially distributes to the liver but is not extensively metabolized in vivo The purpose of this study was to evaluate the disposition of ON 01910. Na employing the isolated perfused rat liver (IPRL) model. The specific goals were to 1) Assess the dose-linearity of ON 01910. Na disposition; 2) Probe the role of the Mrp2 transporter on ON 01910. Na biliary excretion; and 3) Establish the effect of concurrent dosing with oxaliplatin and doxorubicin on ON 01910. Na hepatobiliary disposition. Methods: Perfusion experiments (n=3/group) were performed at 4 doses (0.8, 4, 8, 20 mg), targeting a range of perfusate levels between 10 and 250 ug/ml. ON 01910. Na (10 ug/ml) disposition was then studied in the presence of doxorubicin (2.5 ug/ml) and oxaliplatin (2 ug/ml). IPRL experiments were also conducted using livers from Mrp2 deficient rats. ON 01910. Na was assayed in perfusate and bile samples by HPLC. Results: ON 01910. Na parameter estimates are provided in the table below. The compound displayed nonlinear excretion in the IPRL, and ON 01910. Na disposition was altered in mrp2-deficient rats. The effect of co-administered chemotherapeutic agents is being investigated. Conclusions: ON 01910. Na showed extensive biliary excretion in the IPRL, and IPRL findings correlated with in vivo data in rats. ON 01910. Na biliary transport appears to be mediated in part by Mrp2.ON 01910. Na Disposition in the IPRLaPARAMETERON 01910. Na (µg/ml) 10.050.0100250t1/2 (hr)0.460 (0.0340)0.327 (0.0674)0.585 (0.0810)1.26 (0.318)Cmax (µg/ml)11.3 (1.75)56.1 (7.12)106 (11.2)257 (658)AUC (0-∞) (µg*min/ml)290 (87.1)1480 (73.0)4010 (963)21100 (2580)Cl (ml/min)2.91 (0.753)2.71 (0.134)2.08 (0.557)0.959 (0.125)% Drug Excreted in Bile57.2 (5.04)59.2 (7.40)68.4 (0.870)45.6 (2.66)aData presented as mean (standard deviation) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3534.
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