P169 Human Pharmacokinetics and Mass Balance Study of Beloranib using LC-MS/MS

Philip Inskeep , Inskeep DMPK, East Lyme, CT
Frank Hsieh , Nextcea, Woburn, MA
Nanjun Liu , Nextcea, Woburn, MA
Elizabeth Tengstrand , Nextcea, Woburn, MA
Elena Ryzhikova , Nextcea, Woburn, MA
James Vath , Zafgen, Boston, MI
Jaret Malloy , Zafgen, Boston, MA
Sandy Bertelsen-Purika , Zafgen, Boston, MA
Michael Gartner , Celerion, Lincoln, NE
Title: Human Pharmacokinetics and Mass Balance Study of Beloranib using LC-MS/MS

Authors: Frank Hsieh, Nanjun Liu, Elena Ryzhikova, Elizabeth Tengstrand, James Vath, Jaret Malloy, Sandy Bertelsen-Purika, Michael Gartner, Philip Inskeep*


Beloranib is a synthetic analog of fumagillin that displays potent and selective inhibition of methionine aminopeptidase 2. The objective of this study was to investigate the pharmacokinetics, metabolism, and mass balance of beloranib in humans. Six healthy, adult male subjects received a single subcutaneous injection of 2.4 mg of non-radiolabeled beloranib. Plasma, urine, and feces were collected from all subjects for up to 168 hr (day 8) after dosing. Beloranib and its metabolites were identified and quantitated by LC‑MS/MS. The Cmax of beloranib in plasma was 0.615 ng/mL (range: 0.215 to 1.094 ng/mL). The mean AUClast was 7.31 ng•hr/mL (range: 4.22 to 9.96 ng•hr/mL). The mean recovery of beloranib-related material was 72% of the administered dose, with 19% in the urine and 53% in feces. Unchanged beloranib accounted for only 0.33% of the total recovered dose. Glutathione conjugation of the fumagillol moiety and subsequent degradation accounted for 52.5% of the recovered material. Oxidative and bis-oxidative metabolites of the fumagillol and/or dimethhylaminoethoxy-phenylacrylate moieties represented 10.4%. Ester hydrolysis resulted in fumagillol and its bis-oxidative metabolite accounting for 2.7% of the dose. Epoxide hydrolase rearrangement metabolites accounted for 2.8% of the dose. A low level of glucuronide conjugation was also observed (0.71%). Other minor metabolites were detected, but none represented > 0.1% of the dose.

Keywords: ZGN-440, Beloranib, mass balance, MetAP2 inhibitor, obesity drug