Clinical studies using the boronic acid-based proteasome inhibitor bortezomib have validated the proteasome as a therapeutic intervention point for the treatment of multiple myeloma and non-Hodgkin’s Lymphoma. PR-171 is a novel peptide epoxyketone inhibitor of the 20S proteasome that is currently in phase I clinical trials. Herein, the metabolism, disposition and pharmacokinetics of PR-171 are described. Incubation of 3H-PR-171, labeled in the phenylalanine ring, with freshly prepared rat, monkey and human hepatocyte preparations showed similar metabolite profiles with six predominant radiolabeled metabolites observed in all three species; no metabolites unique to human hepatocytes were detected. The diol of PR-171, formed via epoxide ring hydrolysis, was the most abundant observed metabolite in hepatocyte preparations of each of the three species. Single dose IV bolus PK studies using unlabeled PR-171 in Sprague Dawley rats (2 to 9 mg/kg) and cynomolgus monkeys (1 to 4 mg/kg) showed approximately dose linear PR-171 exposure for both species as measured by plasma AUCs. In both species, PR-171 plasma clearance values (554 and 227 mL/min/kg in rat and monkey, respectively) exceeded hepatic blood flow implying that extrahepatic clearance mechanism(s) must be involved. While the in vitro hepatocyte results suggest that hepatic clearance mechanism(s) are also likely to be involved, in vivo hepatic clearance cannot be conclusively inferred from available data. As predicted by the in vitro hepatocyte results, PR-171 diol was detected at abundant levels in plasma from both rat and monkey. Human pharmacokinetics are similar to those of rat and monkey. Mass balance and tissue distribution were also investigated in rats using 3H-PR-171. Radioactivity was widely distributed following a single IV bolus dosing and reached maximum concentrations at times ranging from 0.5 to 24 hours in different tissues. At 168 hours post-dose, more than 44% of the administrated radioactivity remained in tissues. Excretion via urine and feces accounted for 14% and 18%, respectively, of administered radiation. The distribution of radioactivity may not be indicative of the true distribution of PR-171 as much of the radioactivity may reflect metabolic incorporation of the radiolabel and/or 3H exchange with water.

Disclosures: All authors are employed by Proteolix, Inc.; All authors receive stock options as part of employment by Proteolix, Inc.; All authors receive stock options as part of employment by Proteolix, Inc.

Author notes


Corresponding author