KRAZATI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KRAZATI (KRAZATI).
KRAZATI (adagrasib) is a selective, covalent inhibitor of KRAS G12C. It irreversibly binds to the cysteine residue in the KRAS G12C mutant protein, locking it in an inactive GDP-bound state, thereby inhibiting downstream signaling pathways (e.g., MAPK) and reducing tumor cell proliferation.
| Metabolism | Adagrasib is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. |
| Excretion | Primarily excreted via feces (80% as unchanged drug), with renal excretion accounting for <1% of the dose. |
| Half-life | Terminal elimination half-life is approximately 23 hours, supporting once-daily dosing. |
| Protein binding | Approximately 97% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Volume of distribution is about 210 L, indicating extensive tissue distribution. |
| Bioavailability | Absolute bioavailability is approximately 40% after oral administration, with high-fat meals increasing exposure by 40%. |
| Onset of Action | Onset of clinical effect is not defined; steady-state plasma concentrations are achieved within 8 days of once-daily dosing. |
| Duration of Action | Duration correlates with drug exposure; continuous daily dosing maintains therapeutic concentrations due to long half-life. |
600 mg orally once daily on an empty stomach (no food for at least 2 hours before and 1 hour after dose).
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min). Not recommended for severe renal impairment (eGFR <30 mL/min) or ESRD due to lack of data. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce to 400 mg once daily; Child-Pugh C: not recommended. |
| Pediatric use | Safety and efficacy not established; no approved dosing guidelines. |
| Geriatric use | No specific dose adjustment; monitor for increased gastrointestinal toxicity and electrolyte disturbances due to age-related physiological changes. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KRAZATI (KRAZATI).
| Breastfeeding | No data are available on the presence of adagrasib in human milk, its effects on the breastfed child, or milk production. Because of the potential for serious adverse reactions, breastfeeding is not recommended during treatment and for 1 week after the last dose. The M/P ratio is unknown. |
| Teratogenic Risk | KRAZATI (adagrasib) is a KRAS G12C inhibitor. Based on its mechanism of action and animal studies, there is a potential for embryofetal harm. In pregnant rats, adagrasib caused malformations and embryofetal death at maternal exposures below the human exposure at the recommended dose. There are no adequate and well-controlled studies in pregnant women. First trimester exposure carries risk of major congenital malformations; second and third trimester exposure risks fetotoxicity and growth impairment. Effective contraception is recommended during treatment and for 3 weeks after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
None.
| Precautions | ["Interstitial lung disease (ILD)/pneumonitis: Monitor for new or worsening pulmonary symptoms; withhold, dose reduce, or permanently discontinue if ILD/pneumonitis is confirmed.","Hepatotoxicity: Monitor liver function tests at baseline and periodically; withhold, dose reduce, or permanently discontinue based on severity.","QTc interval prolongation: Monitor ECG and electrolytes; withhold or permanently discontinue if QTc > 500 ms or > 60 ms change from baseline.","GI adverse reactions: Diarrhea, nausea, vomiting; use antiemetics and antidiarrheals as needed.","Drug interactions: Avoid strong CYP3A4 inducers; reduce dose with strong CYP3A4 inhibitors."] |
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| Fetal Monitoring | Monitor for maternal toxicities including hepatotoxicity, gastrointestinal toxicity, QT prolongation, and interstitial lung disease. Perform liver function tests, ECG, and clinical assessment regularly. For fetal monitoring, perform serial ultrasounds to assess growth and anatomy if pregnancy occurs. No specific fetal monitoring is established; manage in consultation with maternal-fetal medicine specialist. |
| Fertility Effects | In animal studies, adagrasib caused impaired fertility in female rats at exposures similar to human exposure, including decreased corpora lutea and implantation sites. Effects on male fertility are unknown. There may be an impact on spermatogenesis based on mechanism. Fertility preservation counseling should be considered for patients of reproductive potential before starting treatment. |