Abstract #1572: Pharmacokinetics of a novel fumagillol conjugate XMT-1107 in the rat
Authors: Alex Yurkovetskiy, Dana Shkolny, Laura Akullian, Mao Yin, Laraine Meyers, Robert Fram, Timothy Lowinger
Journal: Cancer Research (2009)

XMT-1107 is a novel polymer fumagillol derivative, comprised of the small molecule XMT-1191 conjugated to a 70 kDa biodegradable, hydrophilic polyacetal ,  poly(1-hydroxymethylethylene hydroxylmethylformal) (PHF). XMT-1191, the primary release product of XMT-1107, induces antiangiogenic activity by irreversible inhibition of methionine aminopeptidase 2 and exhibits antiproliferative activity at nanomolar concentrations in a HUVEC cell assay. The conjugated drug, XMT-1107, demonstrates improvement in antitumor activity in tumor xenograft models compared to either unconjugated XMT-1191 or the well-known fumagillol derivative TNP-470. In this study we evaluated the pharmacokinetics (PK) of XMT-1107 and its release product XMT-1191 in rat and demonstrated that the selected polymer delivery system extends exposure to conjugated drug and the corresponding drug release product, XMT-1191, while significantly (> 500 fold) reducing XMT-1191 plasma C max . XMT-1107 and XMT-1191 were administered to Sprague-Dawley rats intravenously (iv) as a single bolus at 50.6 mg XMT-1191 equivalents/kg. Blood was collected over 48 hours after administration to determine the highest concentration and extent of exposure (C max  and AUC), volume of distribution (Vd), clearance (CL), and elimination half-life (t 1/2 ). The conjugated and released (free) XMT-1191 in plasma was analyzed by LC-MS/MS. PK of XMT-1107 was monoexponential, with very little to no distribution phase. After immediate C max  (1.1 mg XMT-1191 equivalent/mL), XMT-1107 plasma concentrations declined with a t 1/2  of 22 hours. Observed AUC 0-48  and AUC 0-inf  values were 19,200 hr*\#956;g/mL and 26,700 hr*\#956;g/mL, respectively. XMT-1107 values for CL and Vd were low (1.9 mL/hr and 58 mL respectively) indicating slow renal clearance, low RES uptake and primarily vascular localization of the conjugated drug. The released XMT-1191 exhibited release-dependent PK with an apparent plasma t 1/2  and duration of exposure in good agreement with those of the parent conjugate. The exposure to released XMT-1191 represented \#8804; 0.2 % of the corresponding XMT-1107 AUC values. The comparison of conjugate released XMT-1191 PK with data obtained for XMT-1191 dosed as an iv bolus indicated that conjugation to the polymer reduces C max  and prolongs the duration of exposure to XMT-1191 without substantial difference in overall AUC. Our data suggest that the slow rate of release of XMT-1191 from the polymer conjugate XMT-1107, rather than the PK behavior of XMT-1191 itself, is an important factor contributing to the PK profiles of both XMT-1107 and its release product XMT-1191 in rat plasma. Overall, XMT-1107 provides a water-soluble carrier stabilized form of XMT-1191, which combines extended exposure to drug at reduced circulating concentration of free XMT-1191 with the potential advantages associated with polymer-based targeting of tumor neovasculature.   Citation Information:  In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1572.