Absorption, Distribution, and Binding Profile of ME-401, a Potent and Selective Oral Small-Molecule Inhibitor of Phosphatidylinositol 3-Kinase δ (PI3Kδ) in Animal and B-Cell Lymphoma Models

BACKGROUND: Phosphatidylinositol 3-kinase isoform δ (PI3Kδ) mediates multiple events in lymphocytes, including cell proliferation, survival, and motility. Inhibition of PI3Kδ, with downstream inhibitory effects on cell growth and survival, has been utilized to treat lymphoid malignancies. ME-401 is an oral, once-daily, selective PI3Kδ inhibitor with an optimized pharmacologic profile that is in clinical development for the treatment of B-cell malignancies. OBJECTIVES: This work examined aspects of the pharmacologic profile of ME-401 in preclinical models to investigate the basis of the clinical activity of ME-401 that may differentiate it from other currently approved PI3Kδ inhibitors. METHODS: We determined the ME-401 blood to plasma ratios, permeability, and purified enzyme-binding kinetics. The oral bioavailability and volume of distribution of ME-401 were evaluated in various species. ME-401 concentrations in plasma and tumor and brain tissues were evaluated following oral administration in an A20 syngeneic mouse model of B-cell lymphoma. Idelalisib was used as a reference compound for the measurement of purified enzyme-binding kinetics and concentrations in plasma and tumor in the A20 syngeneic mouse model. RESULTS: Oral administration of ME-401 to dogs resulted in 79% bioavailability compared with intravenous administration. Allometric scaling from rodents, dogs, and nonhuman primates resulted in a predicted human volume of distribution at steady state of 10.75 L/kg. ME-401 was shown to distribute into the lymph in dogs and permeate into cells readily, with a human blood to plasma ratio of 1.4 and ~ 50% retention in the Caco-2 cell monolayer at 1 μM. The high binding affinity and low dissociation rate of ME-401 resulted in an equilibrium dissociation constant (K(D)) of 3.03 × 10(−11) M. Oral administration of ME-401 in an A20 syngeneic mouse model resulted in tumor concentrations 20–30 times higher than plasma concentrations at 4 h after the last dose. By 24 h, the tumor levels had decreased approximately 30–50% compared with levels at 4 h while remaining significantly increased relative to plasma concentrations. ME-401 was also present in brain tissue at 4 and 24 h after the last dose. In comparison, the idelalisib dissociation rate was ~ 100 times higher, resulting in a K(D) of 1.11 × 10(−9) M. Idelalisib tumor concentrations were only approximately three times higher than plasma concentrations at 4 h, while dropping below the limit of quantitation in both tumor and plasma by 24 h. CONCLUSIONS: These data support the capacity of ME-401 to be orally absorbed, distribute to target tissues, enter and accumulate in target cells, and bind to the target with high affinity to exert its mechanism of action. These characteristics underlie the high clinical potency seen in B-cell malignancies that may differentiate ME-401 from other PI3Kδ inhibitors currently approved or in development.