Safety, Pharmacokinetics, and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Following Single Ascending Dose Administration to Healthy Volunteers.

ABSTRACT

PURPOSE: ME-401 is a novel selective inhibitor of phosphatidylinositol 3 kinase p110δ, an enzyme often found overexpressed and overactive in B-cell malignancies. The current study was performed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending oral doses of ME-401 in healthy volunteers. METHODS: This analysis was an open-label, nonrandomized study in healthy male volunteers. Three sequential groups were dosed. Each group received single doses of ME-401 on two occasions; the doses tested ranged from 10 to 150 mg. Blood was drawn at various time points to analyze plasma concentrations of ME-401 and inhibition of basophil activation, a marker of phosphatidylinositol 3 kinase p110δ inhibition. FINDINGS: Fifteen subjects received a single dose of ME-401 on two occasions. Three adverse events that were considered possibly related to the study drug were reported one event of pain, one event of headache, and one event of upper abdominal pain. ME-401 exhibited dose proportionality up to 60 mg, and supra-proportional increases in exposure were observed above doses of 60 mg. In addition, there was a dose-proportional increase in the inhibition of basophil activation up to 60 mg. Mean t1/2 ranged from 9.36 to 29.23 hours across the dose range. A 60 mg dose of ME-401 approached 90% inhibition of basophil activation, and thereafter no further increase to the percent inhibition of basophil activation was observed for higher doses. Once-daily dosing of 60 mg ME-401 was forecasted to result in trough plasma levels exceeding the concentration needed for 90% inhibition of basophil activation. IMPLICATIONS This first-in-human study showed that ME-401 was well tolerated after single doses up to 150 mg. Pharmacologic activity was confirmed after administration of single ascending oral doses of 10 to 150 mg. ME-401 60 mg, administered once daily, was selected as the starting dose for patient studies. ClinicalTrials.gov identifier NCT02521389.