Impact of a High-Fat Meal on the Pharmacokinetics of Sotorasib, a KRAS G12C Inhibitor

Abstract

Sotorasib is a small molecule drug that specifically and irreversibly inhibits the KRAS p.G12C mutant protein. This analysis investigated the impact of a high-calorie high-fat meal on the pharmacokinetics, safety, and tolerability of sotorasib in both healthy volunteers and patients with KRAS G12C advanced solid tumors. Each subject received a single oral dose of 360 or 960 mg of sotorasib under fasted conditions or with a high-fat meal (fed conditions). The geometric least squares means (GLSM) ratios (fed/fasted) for 360 mg of sotorasib C_max and AUC_inf were 1.03 and 1.38, respectively, in healthy volunteers (N = 14). The GLSM ratios (fed/fasted) for C_max and AUC_0-24h were 1.38 and 1.75, respectively, with 360 mg of sotorasib in cancer patients (N = 2). The GLSM ratios (fed/fasted) for C_max and AUC_0-24h were 0.660 and 1.25, respectively, with 960 mg of sotorasib in cancer patients (N = 8). Sotorasib was well tolerated in fast and fed conditions. The impact of a high-fat meal on sotorasib exposure is less than a 2-fold increase or decrease in C_max and AUCs.