070: A Phase I Study of the Absorption, Metabolism & Excretion Following a Single Oral Dose of [14C]-Adagrasib in Healthy Male Subjects

Statement of Purpose: Adagrasib is a potent, selective and covalent KRAS G12C inhibitor that was recently granted accelerated approval by the US FDA for adult patients with KRAS G12C‑mutated locally advanced or metastatic NSCLC, who have received at least one prior systemic therapy. This Phase I, open-label study evaluated the absorption, metabolism and excretion of a single oral dose of 600 mg adagrasib containing approximately 1 μCi of [14C]-adagrasib.

Description of Methods & Materials: Seven healthy male subjects were enrolled and received a single oral dose of 600 mg adagrasib containing approximately 1 μCi of [14C]-adagrasib. Blood collections were obtained from predose through 480 hours postdose for analysis of plasma concentrations of adagrasib, total radioactivity in whole blood and plasma and metabolite profiling and identification in plasma. Urine and feces samples were collected at consecutive intervals from predose through 504 hours postdose for analysis of adagrasib concentration, total radioactivity and metabolite profiling and identification. Noncompartmental analysis was conducted to derive adagrasib PK parameters.

Data & Results: Six subjects completed the study. Following a single oral dose of 600 mg containing approximately 1 μCi of [14C] adagrasib, median t_max for plasma adagrasib was 7 hours. Mean t1/2 of plasma adagrasib, whole blood total radioactivity, and plasma total radioactivity were 18, 36 and 37 hours, respectively. The mean cumulative recovery of total radioactivity was approximately 79.2%. Fecal excretion was the predominant route of elimination for adagrasib, with 74.7% of total radioactivity recovered from feces and 4.49% recovered from urine. The geometric mean AUC_∞ ratio of plasma adagrasib to total radioactivity in plasma was approximately 35%. The geometric mean whole blood/plasma AUC_∞ ratio for total radioactivity was approximately 0.877, indicating no special affinity or preferential binding of adagrasib or its metabolites to blood cells. Only 1.8% of the administered dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance for adagrasib. Adagrasib (parent) was the most abundant plasma, urinary and fecal component. Adagrasib (parent), M55a, M11 and M68 were major plasma components which accounted for 38.33%, 13.58%, 13.40% and 10.96% of total plasma radioactivity exposure, respectively. Metabolites M55a, M11, and M68 do not contribute to adagrasib clinical activity. A single oral dose of 600 mg adagrasib containing approximately 1 μCi of [14C] adagrasib was generally well tolerated, and gastrointestinal disorders were the most frequent adverse events reported.

Interpretation, Conclusion or Significance: The absorption, metabolism and elimination properties of adagrasib were adequately characterized following a single oral dose of 600 mg adagrasib containing 1 μCi of [14C]-adagrasib in healthy male subjects.

Disclosures: This study was funded by Mirati Therapeutics.