Sotorasib is a precise targeted therapeutic agent against KRAS G12C mutations, providing new treatment options for patients with lung cancer and colorectal cancer who have received prior therapy.

I. Introduction to Sotorasib

1. Drug Name and Dosage Form

Sotorasib is administered as oral tablets, available in three strengths: 320 mg, 240 mg and 120 mg.

2. Approved Indications

(1) Monotherapy for locally advanced or metastatic non-small cell lung cancer with KRAS G12C mutation in adult patients who have received at least one prior systemic therapy.

(2) Combination therapy with panitumumab for metastatic colorectal cancer with KRAS G12C mutation in adult patients previously treated with fluoropyrimidine, oxaliplatin and irinotecan chemotherapy.

3. Pre-Treatment Testing

(1) Confirmation of KRAS G12C mutation via an FDA-approved assay is mandatory prior to treatment initiation.

(2) For lung cancer, testing may be performed using tumor tissue or plasma specimens; for colorectal cancer, testing must be conducted on tumor tissue specimens.

II. Mechanism of Action and Drug-Drug Interactions

1. Mechanism of Action

(1) Sotorasib is a KRAS G12C inhibitor.

(2) It forms an irreversible covalent bond with the unique cysteine residue on the KRAS G12C protein, locking the protein in its inactive conformation, blocking downstream signal transduction, while exerting no effect on wild-type KRAS.

(3) In KRAS G12C-mutant tumor cells, sotorasib inhibits cell proliferation and induces apoptosis. In colorectal cancer, combination treatment with panitumumab, an EGFR antagonist, enhances anti-tumor activity.

2. Pharmacokinetic Properties

(1) The median time to peak plasma concentration of sotorasib is approximately 1 hour, with a terminal half-life of around 5 hours.

(2) It is primarily metabolized by the CYP3A4 enzyme. Meanwhile, sotorasib induces CYP3A4, CYP2C8, CYP2C9 and CYP2B6, and inhibits P-glycoprotein and BCRP transporters.

3. Effects of Other Drugs on Sotorasib

(1) Acid-reducing agents (proton pump inhibitors such as omeprazole, H2 receptor antagonists such as famotidine): These agents markedly reduce the plasma concentration of sotorasib (omeprazole reduces peak concentration by 65%), and concomitant use should be avoided. If topical antacids are unavoidable, administration must be separated by more than 4 hours (sotorasib administered first) or more than 10 hours (antacids administered first).

(2) Strong CYP3A4 inducers (e.g., rifampin): Such agents decrease the peak concentration of sotorasib by 35% and area under the curve (AUC) by 51%, and concurrent use is contraindicated.

4. Effects of Sotorasib on Other Drugs

(1) CYP3A4 substrates (e.g., midazolam): Sotorasib reduces the peak concentration of the substrate by 48% and AUC by 53%. Concomitant use with sensitive substrates is not recommended.

(2) P-glycoprotein substrates (e.g., digoxin): Sotorasib increases the peak concentration of the substrate by 91%. Concomitant use with sensitive substrates should be avoided.

(3) BCRP substrates (e.g., rosuvastatin): Sotorasib elevates the peak concentration of the substrate by 70% and AUC by 34%.

III. Management of Missed, Vomited and Overdosed Doses

1. Management of Missed Doses

(1) Administer the medication at a fixed daily time.

(2) If more than 6 hours have elapsed since the scheduled dosing time, skip the missed dose. Resume the regular next dose at the prescribed time on the following day.

(3) Do not take a double dose to compensate for the missed dose under any circumstances.

2. Management of Vomiting After Dosing

(1) Do not take an additional supplementary dose if vomiting occurs following drug administration.

(2) Continue the regular scheduled dose on the subsequent day.

3. Management of Overdosage

(1) Sotorasib overdosage may result in significant hypotension; severe cases may lead to decreased consciousness or even circulatory collapse.

(2) Place the patient in a supine position and seek immediate medical intervention.