Peringatan Keamanan

Toxicity information regarding adagrasib is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as hepatotoxicity, gastrointestinal adverse reactions and QTc interval prolongation.L44361 Symptomatic and supportive measures are recommended.

The carcinogenicity of adagrasib has not been evaluated. In an in vitro bacterial reverse mutation (Ames) assay, adagrasib was not mutagenic. An in vitro chromosomal aberration assay and an in vivo micronucleus assay in rats showed that it was not genotoxic. Studies evaluating the effects of adagrasib on fertility have not been performed. The oral administration of adagrasib to rats for up to 13 weeks induced phospholipidosis at doses higher than 150 mg/kg (approximately 2 times the human exposure at the recommended dose based on AUC). The presence of phospholipidosis led to the increased vacuolation of multiple organs.L44361

Adagrasib

DB15568

small molecule approved investigational

Deskripsi

Adagrasib (MRTX849) is an oral, small-molecule KRAS inhibitor developed by Mirati Therapeutics. KRAS mutations are highly common in cancer and account for approximately 85% of all RAS family mutations.A254941 However, the development of KRAS inhibitors has been challenging due to their high affinity for guanosine triphosphate (GTP) and guanosine diphosphate (GDP), as well as the lack of a clear binding pocket.A187559 Adagrasib targets KRASG12C, one of the most common KRAS mutations, at the cysteine 12 residue and inhibits KRAS-dependent signalling.A254052 In a phase I/IB clinical study that included patients with KRASG12C-mutated advanced solid tumors (NCT03785249), adagrasib exhibited anti-tumor activity. The phase II of the same study showed that in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC), adagrasib was efficient without new safety signals.A254052,A254057,A254946

In February 2022, the FDA accepted a new drug application (NDA) for adagrasib for the treatment of patients with previously treated KRASG12C–positive NSCLC.L43847 In December 2022, the FDA granted accelerated approval to adagrasib for the treatment of KRASG12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.L44361,L44366 Adagrasib joins sotorasib as another KRASG12C inhibitor approved by the FDA.A254062

Struktur Molekul 2D

Berat 604.13
Wujud solid

Peta Jejaring Molekuler
Legenda: Obat • Target • Gen • Enzim • (Panah → menunjukkan arah efek / relasi) • Transporter • Carrier

Profil Farmakokinetik

Waktu Paruh (Half-Life) Adagrasib has a terminal elimination half-life of 23 hours.[L44361]
Volume Distribusi Adagrasib has an apparent volume of distribution of 942 L.[L44361]
Klirens (Clearance) Adagrasib has an apparent oral clearance (CL/F) of 37 L/h.[L44361]

Absorpsi

The AUC and Cmax of adagrasib increase in a dose-proportional manner between 400 mg and 600 mg (0.67 to 1 times the approved recommended dose). At the recommended dose, adagrasib reached steady-state within 8 days, with a 6-fold accumulation. The Tmax of adagrasib is approximately 6 hours. The administration of a high-fat and high-calorie meal (900-1000 calories, 50% from fat) did not have a clinically significant effect on the pharmacokinetics of adagrasib.L44361 Adagrasib has high oral bioavailability and is able to penetrate the central nervous system.A254941

Metabolisme

Following single-dose administration, adagrasib is mainly metabolized by CYP3A4. However, since adagrasib inhibits CYP3A4 following multiple dosing, other enzymes such as CYP2C8, CYP1A2, CYP2B6, CYP2C9, and CYP2D6 contribute to its metabolism at steady-state.L44361

Rute Eliminasi

Adagrasib is eliminated through feces and urine. In patients given a single dose of radiolabeled adagrasib, 75% of the dose was recovered in feces (14% as unchanged), while 4.5% was recovered in urine (2% as unchanged).L44361

Interaksi Makanan

1 Data
  • 1. Take with or without food. High-fat and high-calorie meals do not have a clinically significant effect on adagrasib pharmacokinetics.

Interaksi Obat

733 Data
Darbepoetin alfa The risk or severity of Thrombosis can be increased when Darbepoetin alfa is combined with Adagrasib.
Erythropoietin The risk or severity of Thrombosis can be increased when Erythropoietin is combined with Adagrasib.
Peginesatide The risk or severity of Thrombosis can be increased when Peginesatide is combined with Adagrasib.
Methoxy polyethylene glycol-epoetin beta The risk or severity of Thrombosis can be increased when Methoxy polyethylene glycol-epoetin beta is combined with Adagrasib.
Delamanid Adagrasib may increase the QTc-prolonging activities of Delamanid.
Trazodone The risk or severity of QTc prolongation can be increased when Trazodone is combined with Adagrasib.
Entrectinib The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Entrectinib.
Pitolisant The serum concentration of Adagrasib can be decreased when it is combined with Pitolisant.
Lefamulin Lefamulin may increase the QTc-prolonging activities of Adagrasib.
Hydroxyzine The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Hydroxyzine.
Ziprasidone The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Ziprasidone.
Haloperidol The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Haloperidol.
Fluoxetine The risk or severity of QTc prolongation can be increased when Fluoxetine is combined with Adagrasib.
Ponesimod The risk or severity of bradycardia can be increased when Ponesimod is combined with Adagrasib.
Fexinidazole The risk or severity of adverse effects can be increased when Adagrasib is combined with Fexinidazole.
Mobocertinib The risk or severity of QTc prolongation can be increased when Adagrasib is combined with Mobocertinib.
Lidocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Lidocaine.
Ropivacaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Ropivacaine.
Bupivacaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Bupivacaine.
Cinchocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Cinchocaine.
Dyclonine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Dyclonine.
Procaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Procaine.
Prilocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Prilocaine.
Proparacaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Proparacaine.
Meloxicam The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Meloxicam.
Oxybuprocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Oxybuprocaine.
Cocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Cocaine.
Mepivacaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Mepivacaine.
Levobupivacaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Levobupivacaine.
Diphenhydramine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Diphenhydramine.
Benzocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Benzocaine.
Chloroprocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Chloroprocaine.
Phenol The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Phenol.
Tetrodotoxin The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Tetrodotoxin.
Benzyl alcohol The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Benzyl alcohol.
Capsaicin The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Capsaicin.
Etidocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Etidocaine.
Articaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Articaine.
Tetracaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Tetracaine.
Propoxycaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Propoxycaine.
Pramocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Pramocaine.
Butamben The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Butamben.
Butacaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Butacaine.
Oxetacaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Oxetacaine.
Ethyl chloride The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Ethyl chloride.
Butanilicaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Butanilicaine.
Metabutethamine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Metabutethamine.
Quinisocaine The risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Quinisocaine.
Phenytoin The serum concentration of Adagrasib can be decreased when it is combined with Phenytoin.
Pentobarbital The serum concentration of Adagrasib can be decreased when it is combined with Pentobarbital.
Carbamazepine The serum concentration of Adagrasib can be decreased when it is combined with Carbamazepine.
Mitotane The serum concentration of Adagrasib can be decreased when it is combined with Mitotane.
Primidone The serum concentration of Adagrasib can be decreased when it is combined with Primidone.
Rimexolone The serum concentration of Adagrasib can be decreased when it is combined with Rimexolone.
Rifampin The serum concentration of Adagrasib can be decreased when it is combined with Rifampicin.
Phenobarbital The serum concentration of Adagrasib can be decreased when it is combined with Phenobarbital.
Rifapentine The serum concentration of Adagrasib can be decreased when it is combined with Rifapentine.
Dexamethasone The serum concentration of Adagrasib can be decreased when it is combined with Dexamethasone.
Fosphenytoin The serum concentration of Adagrasib can be decreased when it is combined with Fosphenytoin.
St. John's Wort The serum concentration of Adagrasib can be decreased when it is combined with St. John's Wort.
Midostaurin The serum concentration of Adagrasib can be decreased when it is combined with Midostaurin.
Enzalutamide The serum concentration of Adagrasib can be decreased when it is combined with Enzalutamide.
Lumacaftor The serum concentration of Adagrasib can be decreased when it is combined with Lumacaftor.
Apalutamide The serum concentration of Adagrasib can be decreased when it is combined with Apalutamide.
Nelfinavir The serum concentration of Adagrasib can be increased when it is combined with Nelfinavir.
Indinavir The serum concentration of Indinavir can be increased when it is combined with Adagrasib.
Terfenadine The serum concentration of Adagrasib can be increased when it is combined with Terfenadine.
Ritonavir The serum concentration of Adagrasib can be increased when it is combined with Ritonavir.
Voriconazole The serum concentration of Adagrasib can be increased when it is combined with Voriconazole.
Efavirenz The serum concentration of Adagrasib can be increased when it is combined with Efavirenz.
Ergotamine The serum concentration of Adagrasib can be increased when it is combined with Ergotamine.
Amprenavir The serum concentration of Adagrasib can be increased when it is combined with Amprenavir.
Delavirdine The serum concentration of Adagrasib can be increased when it is combined with Delavirdine.
Methimazole The serum concentration of Adagrasib can be increased when it is combined with Methimazole.
Conivaptan The serum concentration of Conivaptan can be increased when it is combined with Adagrasib.
Tipranavir The serum concentration of Tipranavir can be increased when it is combined with Adagrasib.
Telithromycin The serum concentration of Adagrasib can be increased when it is combined with Telithromycin.
Ketoconazole The serum concentration of Adagrasib can be increased when it is combined with Ketoconazole.
Atazanavir The serum concentration of Adagrasib can be increased when it is combined with Atazanavir.
Amiodarone The serum concentration of Adagrasib can be increased when it is combined with Amiodarone.
Econazole The serum concentration of Adagrasib can be increased when it is combined with Econazole.
Nefazodone The serum concentration of Adagrasib can be increased when it is combined with Nefazodone.
Itraconazole The serum concentration of Adagrasib can be increased when it is combined with Itraconazole.
Clarithromycin The serum concentration of Adagrasib can be increased when it is combined with Clarithromycin.
Saquinavir The serum concentration of Saquinavir can be increased when it is combined with Adagrasib.
Posaconazole The serum concentration of Adagrasib can be increased when it is combined with Posaconazole.
Darunavir The serum concentration of Darunavir can be increased when it is combined with Adagrasib.
Danazol The serum concentration of Adagrasib can be increased when it is combined with Danazol.
Lopinavir The serum concentration of Adagrasib can be increased when it is combined with Lopinavir.
Ditiocarb The serum concentration of Adagrasib can be increased when it is combined with Ditiocarb.
Nilotinib The serum concentration of Adagrasib can be increased when it is combined with Nilotinib.
Telaprevir The serum concentration of Adagrasib can be increased when it is combined with Telaprevir.
Levoketoconazole The serum concentration of Adagrasib can be increased when it is combined with Levoketoconazole.
Lonafarnib The serum concentration of Lonafarnib can be increased when it is combined with Adagrasib.
Boceprevir The serum concentration of Adagrasib can be increased when it is combined with Boceprevir.
Elvitegravir The serum concentration of Adagrasib can be increased when it is combined with Elvitegravir.
Stiripentol The metabolism of Adagrasib can be decreased when combined with Stiripentol.
Curcumin The serum concentration of Adagrasib can be increased when it is combined with Curcumin.
Ribociclib The risk or severity of QTc prolongation can be increased when Ribociclib is combined with Adagrasib.
Danoprevir The serum concentration of Adagrasib can be increased when it is combined with Danoprevir.

Target Protein

GTPase KRas KRAS

Referensi & Sumber

Synthesis reference: Fell, Jay B et al. “Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer.” Journal of medicinal chemistry vol. 63,13 (2020): 6679-6693. doi:10.1021/acs.jmedchem.9b02052
Artikel (PubMed)
  • PMID: 31658955
    Christensen JG, Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, Sudhakar N, Bowcut V, Baer BR, Ballard JA, Burkard MR, Fell JB, Fischer JP, Vigers GP, Xue JY, Gatto S, Fernandez-Banet J, Pavlicek A, Velastegui K, Chao RC, Barton J, Pierobon M, Baldelli E, Patricoin EF, Cassidy DP, Marx MA, Rybkin II, Johnson ML, Ou SI, Lito P, Papadopoulos KP, Janne PA, Olson P: The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov. 2019 Oct 28. pii: 2159-8290.CD-19-1167. doi: 10.1158/2159-8290.CD-19-1167.
  • PMID: 35167329
    Ou SI, Janne PA, Leal TA, Rybkin II, Sabari JK, Barve MA, Bazhenova L, Johnson ML, Velastegui KL, Cilliers C, Christensen JG, Yan X, Chao RC, Papadopoulos KP: First-in-Human Phase I/IB Dose-Finding Study of Adagrasib (MRTX849) in Patients With Advanced KRAS(G12C) Solid Tumors (KRYSTAL-1). J Clin Oncol. 2022 Aug 10;40(23):2530-2538. doi: 10.1200/JCO.21.02752. Epub 2022 Feb 15.
  • PMID: 35658005
    Janne PA, Riely GJ, Gadgeel SM, Heist RS, Ou SI, Pacheco JM, Johnson ML, Sabari JK, Leventakos K, Yau E, Bazhenova L, Negrao MV, Pennell NA, Zhang J, Anderes K, Der-Torossian H, Kheoh T, Velastegui K, Yan X, Christensen JG, Chao RC, Spira AI: Adagrasib in Non-Small-Cell Lung Cancer Harboring a KRAS(G12C) Mutation. N Engl J Med. 2022 Jul 14;387(2):120-131. doi: 10.1056/NEJMoa2204619. Epub 2022 Jun 3.
  • PMID: 31772333
    Romero D: Two new agents target KRAS G12C. Nat Rev Clin Oncol. 2020 Jan;17(1):6. doi: 10.1038/s41571-019-0304-3.
  • PMID: 36387582
    Brazel D, Arter Z, Nagasaka M: A Long Overdue Targeted Treatment for KRAS Mutations in NSCLC: Spotlight on Adagrasib. Lung Cancer (Auckl). 2022 Nov 10;13:75-80. doi: 10.2147/LCTT.S383662. eCollection 2022.
  • PMID: 36448054
    Tian H, Yang Z, He J: Adagrasib: A landmark in the KRAS(G12C)-mutated NSCLC. MedComm (2020). 2022 Nov 25;3(4):e190. doi: 10.1002/mco2.190. eCollection 2022 Dec.

Contoh Produk & Brand

Produk: 3 • International brands: 1
Produk
  • Krazati
    Tablet, film coated • 200 mg • Oral • EU • Approved
  • Krazati
    Tablet, film coated • 200 mg • Oral • EU • Approved
  • Krazati
    Tablet, coated • 200 mg/1 • Oral • US • Approved
International Brands
  • Krazati — Mirati Therapeutics

Sekuens Gen/Protein (FASTA)

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