THE ABSOLUTE BIOAVAILABILITY AND ABSORPTION, METABOLISM, AND EXCRETION OF IPATASERTIB, A POTENT AND HIGHLY SELECTIVE AKT INHIBITOR .

Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule, ATP-competitive Akt inhibitor being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using 14 C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (Period 1) and mass balance and metabolite profiling (Period 2). In Period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by 80 μg (800 nCi) intravenous dose of [ 14 C]-ipatasertib. In Period 2, subjects received a single oral dose containing approximately 200 mg (100 μCi) of [ 14 C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the 14 C microtracer IV PK in Period 1 and fully profile plasma radioactivity in Period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives following oral and IV administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. Following a single oral dose of [ 14 C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was N-dealkylation mediated by CYP3A, and minor pathways were oxidative by P450s and aldehyde oxidase. Significance Statement The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small molecule Akt inhibitor. An ultrasensitive radioactive counting method, accelerator mass spectrometry (AMS) was successfully applied for 14 C-microtracer absolute bioavailability determination and plasma metabolite profiling.