Abstract #2921: Pharmacokinetics and pharmacodynamics of a selective proteasome inhibitor MLN9708 in nonclinical species following either intravenous or oral administration

MLN9708 is Millennium\#8217;s second generation proteasome inhibitor, following bortezomib for Injection, a first-in-class proteasome inhibitor that is currently used for the treatment of multiple myeloma and relapsed mantle cell lymphoma. MLN9708 will be in clinical development for evaluation of safety and effectiveness in both hematologic and non-hematologic malignancies. MLN9708 immediately hydrolyzes to MLN2238, the biologically active form, upon exposure to aqueous solutions or plasma. MLN9708 was developed as a clinical formulation. In the present studies, the pharmacokinetics (PK) and pharmacodynamics (PD) of MLN2238 were investigated in SCID mice bearing human CWR22 tumor xenografts, Spague-Dawley rats, Beagle dogs and Cynomolgus monkeys following either intravenous or oral administration of a solution of MLN2238. These results demonstrate that 1) MLN2238 had a very low blood clearance (CLb, 0.0087 - 0.050 L/hr/kg) and a moderate blood volume of distribution at steady-state (Vss,b,1.26 - 2.78L/kg) with a long terminal half-life (t1/2) >24 hr in all species tested; 2) MLN2238 demonstrated moderate to excellent oral bioavailability in two species studied (rats and dogs, 40-80%); and 3) MLN2238 showed lower in vivo blood EC50s in rats (114 ng/mL), dogs (134 ng/mL), and monkeys (97.6 ng/mL) than in the mouse (257 ng/mL). In addition, at a well-tolerated dose of MLN2238, rats, dogs, and monkeys showed blood 20S inhibition at levels similar to those observed in the tumor-bearing mouse model at efficacious doses, and 4) MLN2238 showed higher proteasome inhibition in the tumor tissues than in the blood, consistent with improved antitumor activities compared to bortezomib in mouse tumor models. In conclusion, the nonclinical studies demonstrated good PK/PD properties of MLN2238 across several species and support clinical development of MLN9708. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2921.