Identification

Summary

Adagrasib is a KRAS inhibitor indicated for the treatment of locally advanced or metastatic KRAS G12C-mutated non-small cell lung cancer in patients who have received at least one prior systemic therapy.

Brand Names
Krazati
Generic Name
Adagrasib
DrugBank Accession Number
DB15568
Background

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.5 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.1 Adagrasib targets KRASG12C, one of the most common KRAS mutations, at the cysteine 12 residue and inhibits KRAS-dependent signalling.2 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.2,3,6

In February 2022, the FDA accepted a new drug application (NDA) for adagrasib for the treatment of patients with previously treated KRASG12C–positive NSCLC.7 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.8,9 Adagrasib joins sotorasib as another KRASG12C inhibitor approved by the FDA.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 604.13
Monoisotopic: 603.2524793
Chemical Formula
C32H35ClFN7O2
Synonyms
  • ((2s)-4-(7-(8-chloronaphthalen-1-yl)-2-(((2s)-1- methylpyrrolidin-2-yl)methoxy)-5,6,7,8- tetrahydropyrido(3,4-d)pyrimidin-4-yl)-1-(2-fluoroprop2-enoyl)piperazin-2-yl)acetonitrile
  • 2-piperazineacetonitrile, 4-(7-(8-chloro-1-naphthalenyl)-5,6,7,8-tetrahydro-2-(((2s)-1-methyl-2-pyrrolidinyl)methoxy)pyrido(3,4-d)pyrimidin-4-yl)-1-(2-fluoro-1-oxo-2-propen-1-yl)-, (2s)-
  • KRAS G12C inhibitor MRTX849
External IDs
  • MRTX-849
  • MRTX849

Pharmacology

Indication

Adagrasib is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who have received at least one prior systemic therapy.8

This indication is approved under accelerated approval based on objective response rate (ORR) and duration of response (DOR). Continued approval for this indication may be contingent upon verification and description of a clinical benefit in a confirmatory trial(s).8

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

The exposure-response relationship and pharmacodynamic response time course of adagrasib have not been elucidated. The use of adagrasib can cause QTc interval prolongation. The increase in QTc is concentration-dependent. In patients given 600 mg of adagrasib twice daily, the mean QTcF change from baseline (ΔQTcF) was 18 ms at the mean steady-state maximum concentration.8 The use of adagrasib can also lead to severe gastrointestinal adverse reactions, hepatotoxicity and interstitial lung disease/pneumonitis.8

Mechanism of action

In normal cells, KRAS is activated by binding to guanosine triphosphate (GTP), and this promotes the activation of the MAP kinase pathway and intracellular signal transduction. When GTP is hydrolyzed to guanosine diphosphate (GDP), KRAS is inactivated. This mechanism works as an "on"/"off" system that regulates cell growth. The substitution of Gly12 by cysteine in KRAS (KRASG12C) impairs GTP hydrolysis, and maintains KRAS in its active form. Therefore, the presence of this mutation leads to uncontrolled cellular proliferation and growth, as well as malignant transformation.1 Adagrasib is a covalent inhibitor of KRASG12C that irreversibly and selectively binds and locks KRASG12C in its inactive, guanosine diphosphate–bound state.2 Therefore, the use of adagrasib inhibits tumor cell growth and viability in cancers with KRASG12C mutations with minimal off-target activity.8

TargetActionsOrganism
AGTPase KRas
inhibitor
Humans
Absorption

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.8 Adagrasib has high oral bioavailability and is able to penetrate the central nervous system.5

Volume of distribution

Adagrasib has an apparent volume of distribution of 942 L.8

Protein binding

In vitro, adagrasib has a human plasma protein binding of 98%.8

Metabolism

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.8

Route of elimination

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).8

Half-life

Adagrasib has a terminal elimination half-life of 23 hours.8

Clearance

Adagrasib has an apparent oral clearance (CL/F) of 37 L/h.8

Adverse Effects
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Toxicity

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.8 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.8

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AlfentanilThe serum concentration of Alfentanil can be increased when it is combined with Adagrasib.
AlprazolamThe serum concentration of Alprazolam can be increased when it is combined with Adagrasib.
AmiodaroneThe serum concentration of Adagrasib can be increased when it is combined with Amiodarone.
AmprenavirThe serum concentration of Adagrasib can be increased when it is combined with Amprenavir.
ApalutamideThe serum concentration of Adagrasib can be decreased when it is combined with Apalutamide.
AprepitantThe serum concentration of Aprepitant can be increased when it is combined with Adagrasib.
ArticaineThe risk or severity of methemoglobinemia can be increased when Adagrasib is combined with Articaine.
AtazanavirThe serum concentration of Adagrasib can be increased when it is combined with Atazanavir.
AtomoxetineThe serum concentration of Atomoxetine can be increased when it is combined with Adagrasib.
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Adagrasib.
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Food Interactions
  • Take with or without food. High-fat and high-calorie meals do not have a clinically significant effect on adagrasib pharmacokinetics.

Products

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International/Other Brands
Krazati (Mirati Therapeutics)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KrazatiTablet, coated200 mg/1OralMirati Therapeutics, Inc2022-12-12Not applicableUS flag

Categories

Drug Categories
Classification
Not classified
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
8EOO6HQF8Y
CAS number
2326521-71-3
InChI Key
PEMUGDMSUDYLHU-ZEQRLZLVSA-N
InChI
InChI=1S/C32H35ClFN7O2/c1-21(34)31(42)41-17-16-40(18-23(41)11-13-35)30-25-12-15-39(28-10-4-7-22-6-3-9-26(33)29(22)28)19-27(25)36-32(37-30)43-20-24-8-5-14-38(24)2/h3-4,6-7,9-10,23-24H,1,5,8,11-12,14-20H2,2H3/t23-,24-/m0/s1
IUPAC Name
SMILES
[H][C@@]1(COC2=NC3=C(CCN(C3)C3=CC=CC4=C3C(Cl)=CC=C4)C(=N2)N2CCN(C(=O)C(F)=C)[C@@]([H])(CC#N)C2)CCCN1C

References

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

General References
  1. 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. [Article]
  2. 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. [Article]
  3. 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. [Article]
  4. Romero D: Two new agents target KRAS G12C. Nat Rev Clin Oncol. 2020 Jan;17(1):6. doi: 10.1038/s41571-019-0304-3. [Article]
  5. 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. [Article]
  6. 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. [Article]
  7. Cancer Network: New Drug Application for Adagrasib Accepted by FDA for KRAS G12C+ NSCLC [Link]
  8. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]
  9. PR NewsWire: Mirati Therapeutics Announces U.S. FDA Accelerated Approval of KRAZATI (adagrasib) as a Targeted Treatment Option for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation [Link]
ChemSpider
81409342
BindingDB
50539763
RxNav
2625882
ChEMBL
CHEMBL4594350
Wikipedia
Adagrasib

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3RecruitingTreatmentAdvanced Colorectal Cancer / Metastatic Colorectal Cancer (CRC)1
3RecruitingTreatmentAdvanced Non-Small Cell Lung Cancer (NSCLC) / Metastatic Non-Small Cell Lung Cancer1
2Not Yet RecruitingTreatmentKRAS P.G12C / Stage IV Non-small Cell Lung Cancer (NSCLC)1
2Not Yet RecruitingTreatmentResectable Non-small Cell Lung Cancer1
2RecruitingTreatmentAdvanced Non-Small Cell Lung Cancer (NSCLC) / Metastatic Lung Cancer1
2, 3RecruitingTreatmentAdvanced Non-Small Cell Lung Cancer (NSCLC) / Metastatic Non-Small Cell Lung Cancer1
1Active Not RecruitingTreatmentAdvanced or Metastatic Solid Tumor1
1Active Not RecruitingTreatmentAdvanced Solid Tumors1
1CompletedTreatmentAdvanced Malignant Neoplasm / Colon Cancer / Malignant Neoplasm of Lung / Malignant Neoplastic Disease / Metastatic Cancer1
1Not Yet RecruitingTreatmentPancreatic Metastatic Cancer1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, coatedOral200 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)From > 262 mg/mL to < 0.010 mg/mLFDA label
Predicted Properties
PropertyValueSource
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
Adagrasib binds to G12C-mutated KRAS, not its wild-type form.
General Function
Protein complex binding
Specific Function
Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation (PubMed:23698361, PubMed:22711838).
Gene Name
KRAS
Uniprot ID
P01116
Uniprot Name
GTPase KRas
Molecular Weight
21655.67 Da
References
  1. 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. [Article]
  2. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. FDA Approved Drug Products: KRAZATI (adagrasib) tablets for oral use [Link]

Drug created at November 01, 2019 18:31 / Updated at December 17, 2022 02:23