Absorption, single-dose and steady-state metabolism, excretion, and pharmacokinetics of adagrasib, a KRASG12C inhibitor

This study investigated absorption, metabolism, and excretion of adagrasib after a single oral 600 mg dose (1 µCi [¹⁴C]-adagrasib) in 7 healthy subjects and compared the metabolite profile to the profile at steady-state in 4 patients dosed at 600 mg twice daily.

Plasma, urine, and feces were collected post [¹⁴C]-adagrasib administration and total radioactivity and pooled sample metabolite profiles were determined. Adagrasib pharmacokinetics were determined in plasma and urine. The steady-state plasma metabolite profile was examined in patients and in vitro studies were performed to understand adagrasib’s potential to inhibit CYP enzymes and identify CYPs involved in its metabolism.

The total mean recovery of the administered radioactivity was 79.2%, with 74.7% and 4.49% of total radioactivity recovered from feces and urine, respectively. Only 1.8% of the dose was excreted in urine as unchanged adagrasib, indicating negligible renal clearance. Adagrasib, M55a, M11, and M68 were major plasma components accounting for 38.3%, 13.6%, 13.4%, and 11.0% of the total plasma radioactivity exposure, respectively. Metabolite M55a was not detected in plasma at steady state where only M68 (24%) and M11 (17.1%) were abundant. In vitro data showed that CYP3A4 (72%) and CYP2C8 (28%) are main contributors to metabolism and adagrasib is a time-dependent inhibitor of CYP3A4.

Elimination of adagrasib is mainly by fecal excretion. Adagrasibs altered metabolite profile at steady state is likely due to CYP3A4 autoinhibition. The abundant steady-state plasma metabolites, M68 and M11, are not human specific and do not contribute significantly to the pharmacological activity of adagrasib.