Adagrasib

BRAND NAMES

Krazatiq – marketed for KRAS G12C-mutated cancers, particularly non-small cell lung cancer (NSCLC). 

MECHANISM OF ACTION

Adagrasib is a selective, covalent inhibitor of the KRAS G12C mutant protein, which is commonly found in cancers such as non-small cell lung cancer and colorectal cancer. KRAS normally acts as a molecular switch, cycling between an active GTP-bound state and an inactive GDP-bound state to regulate cell growth and survival. In tumors with the G12C mutation, KRAS is often constitutively active, driving uncontrolled cell proliferation. Adagrasib binds covalently to the cysteine residue at position 12 of KRAS G12C in its inactive GDP-bound form, preventing it from becoming active. This inhibition blocks downstream signaling pathways, including MAPK/ERK and PI3K/AKT, ultimately reducing tumor cell growth and survival while sparing normal KRAS proteins, minimizing off-target effects.

PHARMACOKINETICS

Absorption

Adagrasib is orally administered and is absorbed through the gastrointestinal tract. After oral dosing, it reaches peak plasma concentrations (Tmax) typically around 6–8 hours. Food has a minimal effect on overall exposure, although taking it with a meal may slightly delay absorption. The drug exhibits moderate bioavailability, and its pharmacokinetics support twice-daily dosing to maintain therapeutic plasma levels.

Distribution

Adagrasib (Krazati) has a large apparent volume of distribution (Vd) of approximately 942 L.

Metabolism

Adagrasib is primarily metabolized in the liver, mainly by the CYP3A4 enzyme, into inactive metabolites. This metabolic pathway means that drugs that strongly induce or inhibit CYP3A4 can significantly affect adagrasib levels. Metabolism helps regulate the drug’s systemic exposure and contributes to its elimination from the body.

Elimination

Adagrasib is eliminated mainly through feces, with a smaller portion excreted in the urine. Its half-life of approximately 24 hours supports twice-daily dosing, and clearance is influenced by hepatic metabolism via CYP3A4. This elimination profile allows steady plasma concentrations to be maintained for effective inhibition of KRAS G12C.

PHARMACODYNAMICS

Adagrasib selectively and irreversibly inhibits the KRAS G12C mutant protein, preventing it from activating downstream signaling pathways such as MAPK/ERK and PI3K/AKT that drive tumor cell proliferation and survival. By locking KRAS G12C in its inactive GDP-bound state, adagrasib reduces tumor growth and can induce cancer cell death. Pharmacodynamic studies show dose-dependent inhibition of KRAS signaling, with corresponding decreases in tumor size and activity in patients with KRAS G12C-mutated cancers. The drug’s effects are sustained with twice-daily dosing, correlating with maintained plasma concentrations above the target inhibitory threshold.

ADMINISTRATION

Adagrasib is administered orally in the form of tablets. The recommended dosing schedule is twice daily, with or without food, to maintain effective plasma levels. Patients are advised to swallow the tablets whole and to follow any specific guidance regarding dose adjustments in cases of liver or kidney impairment, drug interactions, or adverse effects.

DOSAGE AND STRENGTH

Adagrasib is typically administered at a dose of 600 mg orally twice daily. It is available in 150 mg tablets, so the standard regimen involves taking four tablets per dose. Dose adjustments may be required for patients experiencing adverse reactions or those with moderate hepatic or renal impairment, following a healthcare provider’s guidance.

DRUG INTERACTIONS

Adagrasib is metabolized by CYP3A4, so inhibitors may increase its levels and inducers may reduce its effectiveness. It also weakly inhibits P-glycoprotein, potentially affecting other medications.

FOOD INTERACTIONS

Adagrasib can be taken with or without food, as meals have minimal impact on its overall absorption. High-fat or large meals may slightly delay the time to peak concentration but do not significantly affect drug exposure.

CONTRAINDICATIONS

Adagrasib is contraindicated in patients with a known hypersensitivity to adagrasib or any of its excipients. Caution is also advised in individuals with severe hepatic impairment or those taking strong CYP3A4 inducers, as these conditions can significantly alter drug levels and increase the risk of toxicity.

SIDE EFFECTS

Common side effects:

• Diarrhea.

• Nausea.

• Vomiting.

• Fatigue.

• Elevated liver enzymes.

• Decreased appetite.

Less frequent but serious adverse effects:

• Hepatotoxicity.

• Interstitial lung disease.

• QT interval prolongation.

TOXICITY

Adagrasib’s toxicity profile is generally manageable but can include hepatotoxicity, gastrointestinal toxicity (diarrhea, nausea, vomiting), and cardiac effects such as QT interval prolongation. Severe or prolonged toxicities may requiredose interruption, reduction, or discontinuation. Close monitoring of liver function, electrolytes, and cardiac status is recommended during treatment to minimize risks.