Sotorasib is the first approved KRAS G12C-targeted therapy, indicated for the treatment of non-small cell lung cancer and colorectal cancer with KRAS G12C mutations.
Drug Interactions with Sotorasib
Sotorasib is primarily metabolized through non-enzymatic binding and CYP3A oxidative metabolism. It is a substrate and inducer of CYP3A4, and an inhibitor of P-glycoprotein (P-gp). In vitro studies show that it can induce CYP2C8, CYP2C9, and CYP2B6, and inhibit breast cancer resistance protein (BCRP), but does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.
Drugs Affecting Hepatic Microsomal Enzymes
Strong CYP3A4 inducers: May reduce systemic exposure of sotorasib, decreasing efficacy. Avoid concomitant use.
CYP3A4 substrates: May reduce plasma concentrations of CYP3A4 substrate drugs, decreasing their efficacy. Avoid concomitant use with sensitive CYP3A4 substrates that have a narrow therapeutic window. If unavoidable, refer to the substrate drug's prescribing information for dose adjustment.
Drugs Affecting Transport Systems
P-gp substrates: May increase plasma concentrations of P-gp substrate drugs, increasing toxicity. Avoid concomitant use with P-gp substrates where even minor concentration changes may lead to serious toxicity. If unavoidable, refer to the substrate drug's prescribing information for dose adjustment.
BCRP substrates: May increase plasma concentrations of BCRP substrate drugs, increasing toxicity. Monitor for adverse reactions and consider dose adjustment when used together.
Drugs Affecting Gastric Acidity
May reduce systemic exposure of sotorasib. Avoid concomitant use of proton pump inhibitors, H2-receptor antagonists, and locally acting antacids. If co-administration of a locally acting antacid is unavoidable, administer sotorasib 4 hours before or 10 hours after the antacid.
Specific Drugs with Documented Interactions with Sotorasib
1. Locally acting antacids: May reduce systemic exposure of sotorasib. Avoid concomitant use. If unavoidable, administer sotorasib 4 hours before or 10 hours after the antacid.
2. Digoxin: As a P-gp substrate, co-administration with sotorasib increases digoxin peak concentration and AUC by 91% and 21%, respectively. Avoid concomitant use. If unavoidable, adjust digoxin dosage.
3. Famotidine: Under fed conditions, when famotidine is given 10 hours before and 2 hours after a single dose of sotorasib, sotorasib peak concentration and AUC are reduced by 35% and 38%, respectively. Avoid concomitant use.
4. Metformin: As a MATE1 and MATE2-K substrate, co-administration with sotorasib did not significantly change its exposure.
5. Midazolam: As a sensitive CYP3A4 substrate, co-administration with sotorasib reduces midazolam peak concentration and AUC by 48% and 53%, respectively. Avoid concomitant use. If unavoidable, adjust midazolam dosage.
6. Omeprazole: Under fed conditions, it reduces sotorasib peak concentration and AUC by 65% and 57%, respectively; under fasting conditions, by 57% and 42%. Avoid concomitant use.
7. Rifampin: As a strong CYP3A4 inducer, it reduces sotorasib peak concentration and AUC by 35% and 51%, respectively. Avoid concomitant use.
8. Rosuvastatin: As a BCRP substrate, co-administration with sotorasib increases its peak concentration and AUC by 70% and 34%, respectively. Monitor for adverse reactions and adjust rosuvastatin dosage.
