Abstract 4522: Pharmacokinetic evaluation of a novel anti-angiogenic molecule named JFD-WS in Balb/c mice

Abstract

JFD is a novel anti-angiogenic compound which mediates its action by blocking Vascular Endothelial Growth Factor Receptors and associated kinase activity, thereby arresting tumor angiogenesis and growth. The original JFD has been modified into a water soluble form (JFD-WS) to increase bioavailability and distribution during the in vivo pre-clinical testing in mouse model. Through both in vitro and in vivo testing, we have confirmed its anti-angiogenic and cytoreductive properties and are currently establishing its pharmacokinetic (PK) properties. The absorption, distribution and elimination of JFD-WS were determined by measuring the plasma and urine concentrations after intraperitoneal (i.p.) and oral administration in Balb/c mice. Following i.p. administration of JFD-WS (100 mg/kg body weight), the plasma samples were collected at 2.5, 5, 10, 15, 30, 60, 120, 1440 mins and the urine samples were collected at 15, 30, 60, 120, 1440 mins. The JFD-WS was extracted using a simple liquid extraction procedure and the concentrations in the plasma and urine were analyzed using HPLC method. Our experiments showed that JFD-WS can reach peak plasma concentration after 15 mins and a maximum elimination in urine was observed after 30 mins of i.p. injection. The compound was undetectable in both plasma and urine after 24 hours. Further analysis of plasma levels of JFD-WS using standard PK parameters has led us to hypothesize that JFD-WS may follow a two compartment kinetic model, according to which the molecule may enter the liver through the portal vein after absorption from the peritoneal cavity. During drug distribution, JFD-WS seems to enter the first compartment, including blood circulation, and then reaches the second compartment i.e., the rest of the body till equilibrium is attained. It is further speculated that the first phase of CYP450 system mediated metabolism may not be very extensive since our compound is in water soluble form. Finally, a majority of the molecule is excreted out by glomerular filtration in urine while a small portion is removed through the feces as well. Derived from an established PK formula, the half-life (t½) of our JFD-WS molecule was found to be around 33 mins. A high volume of distribution calculated for JFD-WS leads us to assume that it may distribute largely in extravascular regions such as muscles and tissues, while a high clearance rate could contribute to the lower toxicity of the compound. This hypothesis is further supported by our observations found in the in vivo systems, wherein JFD-WS is highly effective in causing tumor inhibition with minimal toxicity. Thus, the results of our study confirm that i.p. administration allows for reasonable distribution of JFD-WS to the tumor sites within a shorter duration of time that can produce cytoreductive effect. (The Royal Dames of Cancer Research Inc., Ft. Lauderdale Florida is gratefully acknowledged for their generous financial support).

Citation Format: Manasa Subbarao, Sivanesan Dhandayuthapani, Mortatha Albassam, Appu Rathinavelu. Pharmacokinetic evaluation of a novel anti-angiogenic molecule named JFD-WS in Balb/c mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4522. doi:10.1158/1538-7445.AM2015-4522