PII-120 - IMPACT OF MODERATE OR SEVERE HEPATIC IMPAIRMENT ON THE PHARMACOKINETICS OF SOTORASIB AND ITS METABOLITES

M. McComb¹, P. Cardona², C. Sampson³, J. Purkis¹, J. Wahlstrom¹, W. Kormany¹, B. Houk⁴; ¹Amgen, ²Amgen, Inc, ³Amgen, , United States, ⁴Clinical Pharmacology Modeling and Simulation, Amgen.

Background: Sotorasib is a small molecule KRASG12C inhibitor approved for the treatment of KRASG12C-mutated locally advanced or metastatic NSCLC in adult patients. This study evaluated the pharmacokinetics of sotorasib and its metabolites to determine the need for dosing adjustments in subjects with moderate hepatic impairment (HI, Child-Pugh B) and severe HI (Child-Pugh C).

Methods: This Phase 1, parallel-arm, multi-center (US), open-label, non-randomized study included 7 evaluable normal hepatic function (HF), 7 evaluable moderate HI and 4 evaluable severe HI subjects. All subjects received a single oral dose of 960 mg sotorasib administered under fasted conditions. Blood samples were collected predose and up to 168 hours post dose. Total sotorasib and sotorasib metabolites M10 (cysteine adduct of sotorasib, inactive metabolite), M18 (hydroxylated form of sotorasib, >3-fold less potent than sotorasib) and M24 (formed by the bond cleavage at the piperazine acrylamide moiety, inactive metabolite) plasma concentrations were measured using a validated high-performance liquid chromatography tandem mass spectrometry method. PK parameters were estimated using non-compartmental methods. Safety and tolerability were monitored throughout the study.

Results: Sotorasib concentrations were similar in all groups. Metabolite-to-parent ratio geometric mean (arithmetic %CV) of AUClast for subjects with normal HF, moderate HI, and severe HI for M10 were 0.973 (51.8%), 3.32 (54.7%), and 9.09 (23.0%), for M18 were 0.138 (29.5%), 0.150 (36.9%), and 0.0503 (44.5%), and for M24 were 0.323 (69.7%), 0.564 (50.3%), and 1.07 (21.2%), respectively. Arithmetic mean t1/2 values for all metabolites were similar in subjects with normal HF and subjects with moderate or severe HI.
Single doses of sotorasib were safe and well tolerated when administered to subjects with normal HF and subjects with moderate or severe HI.

Conclusion: Pharmacokinetics of sotorasib are unaffected by moderate and severe hepatic impairment, Sotorasib metabolite formation is shifted by hepatic impairment, resulting in increased M10 formation and decreased M18 formation. The effect of moderate or severe HI on sotorasib metabolite pharmacokinetics is minimal and no dose adjustments are recommended for sotorasib in moderate or severe HI patients.