Abstract #3604: A phase I single-rising dose study evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of an oral akt inhibitor in healthy male volunteers

Background: MK-2206 is an orally active, allosteric Akt inhibitor which in preclinical models showed antitumor effects. Methods: Twenty-four healthy, male subjects participated in a Phase I randomized, double-blind, placebo-controlled, sequential-panel, multiple-period, rising single oral dose study of MK-2206. Eight (8) subjects were assigned to each of 3 panels (Panels A, B, and C) where in each treatment period in a panel the same 6 subjects received MK-2206 and 2 subjects received placebo after an overnight fast. The volunteers were administered single doses from 0.25 to 100 mg and blood samples were collected predose and at prespecified postdose timepoints for pharmacokinetic and pharmacodynamic (whole blood inhibition of phospho Akt) assays. Results: Single doses of MK-2206, up to 100 mg, were found to be generally well tolerated. No serious clinical or laboratory adverse experience was reported. The most commonly reported adverse experiences were headache, common cold, and diarrhea. One subject was discontinued from the study due to the clinical adverse experience of blurry vision which resolved. There were no clinically meaningful changes in laboratory safety tests and ECG evaluations. Preliminary pharmacokinetic results found that orally administered MK-2206 was readily absorbed with a median T max of 6 to 8 hours. The median half-life was 55 to 78 hours. AUC 0-\#8734; and C max displayed dose proportional behavior from 2-mg to 100-mg. Preliminary pharmacodynamic results found that single doses of 40-, 80- and 100-mg MK-2206 inhibited Akt in whole blood to a greater extent than placebo. Maximum Akt inhibition occurred at 6 hours postdose for both the 80- and 100-mg doses with mean plasma concentrations of >65 nM. There was evidence of Akt inhibition from 2 through 24 hours. Conclusion: MK-2206 is an antitumor agent which was generally well tolerated following single dose administration to healthy subjects. MK-2206 displays dose proportional pharmacokinetics with clear evidence of Akt inhibition. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 3604.