Impact of Sotorasib, a KRAS G12C Inhibitor, on the Pharmacokinetics and Therapeutic Window of Digoxin, a P‐Glycoprotein Substrate

Abstract Sotorasib is a small‐molecule Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C inhibitor indicated for the treatment of KRAS G12C‐driven cancers. KRAS G12C is a common mutation in solid tumors, including non‐small cell lung cancer. In vitro studies suggested that sotorasib is a weak inhibitor of P‐glycoprotein transporter. Digoxin is a known substrate for P‐glycoprotein. The primary objective of this study was to assess the impact of sotorasib on digoxin pharmacokinetics in healthy subjects. This Phase 1, open‐label, fixed‐sequence study enrolled 14 healthy subjects. Each subject received 0.5 mg of digoxin on Day 1 and 960 mg of sotorasib followed by 0.5 mg of digoxin on Day 7. Blood samples for digoxin pharmacokinetics were collected before dosing and up to 144 hours after the digoxin dose. Digoxin median time to maximum observed plasma concentration and mean terminal half‐life were similar following coadministration of digoxin with sotorasib compared with those of digoxin alone. Geometric mean digoxin area under the concentration‐time curve from time 0 extrapolated to infinity following coadministration of digoxin with sotorasib (40.3 h•ng/mL) was similar to that of digoxin alone (33.2 h•ng/mL). Geometric mean digoxin maximum observed plasma concentration following coadministration of digoxin with sotorasib (3.64 ng/mL) was higher compared with that of digoxin alone (1.90 ng/mL). Coadministration of digoxin and sotorasib did not impact sotorasib exposure. Single doses of 0.5 mg of digoxin were safe and well tolerated when administered alone or coadministered with 960 mg of sotorasib. Coadministration of digoxin with a single dose of sotorasib increased digoxin area under the concentration‐time curve from time 0 extrapolated to infinity and maximum observed plasma concentration by factors of 1.21 and 1.91, respectively, compared with digoxin alone.