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.

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.