Osimertinib

Identification

Summary

Osimertinib is a tyrosine kinase inhibitor used in the treatment of certain types of non-small cell lung carcinoma.

Brand Names
Tagrisso
Generic Name
Osimertinib
DrugBank Accession Number
DB09330
Background

Osimertinib is an oral, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug developed by AstraZeneca Pharmaceuticals.1,9 Its use is indicated for the treatment of metastatic non-small cell lung cancer (NSCLC) in cases where tumour EGFR expression is positive for the T790M mutation as detected by FDA-approved testing and which has progressed following therapy with a first-generation EGFR tyrosine kinase inhibitor. Approximately 10% of patients with NSCLC have a rapid and clinically effective response to EGFR-TKIs due to the presence of specific activating EGFR mutations within the tumour cells.2 More specifically, deletions around the LREA motif in exon 19 and exon 21 L858R point mutations are correlated with response to therapy.3

Development of third-generation EGFR-TKIs, such as osimertinib, has been in response to altered tumour resistance patterns following treatment and toxic side effects that impact patient quality of life. Treatment with first-generation EGFR-TKIs (gefitinib and erlotinib) has been associated with the development of resistance through activating mutations in the EGFR gene. Second-generation EGFR-TKIs (afatinib and dacomitinib) were then developed to be more potent inhibitors, although their use is associated with increased toxicity through nonspecific targeting of wild-type EGFR. In contrast, third-generation inhibitors are specific for the gate-keeper T790M mutations which increases ATP binding activity to EGFR and result in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.1,2,6

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 499.619
Monoisotopic: 499.269573331
Chemical Formula
C28H33N7O2
Synonyms
  • Mereletinib
  • N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
  • Osimertinib
  • Osimertinibum
External IDs
  • AZD 9291
  • AZD-9291
  • AZD9291

Pharmacology

Indication

Osimertinib is indicated for the:

  • adjuvant treatment of non-small cell lung cancer (NSCLC) after tumour resection in adult patients whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.10
  • first-line treatment of adult patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations.10
  • in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced or metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.10
  • treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.10
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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used as adjunct in combination to treatLocally advanced non-small cell lung cancerRegimen in combination with: Pemetrexed (DB00642)•••••••••••••••••••••••
Used as adjunct in combination to treatLocally advanced non-small cell lung cancerRegimen in combination with: Pemetrexed (DB00642)•••••••••••••••••••••••
Used as adjunct in combination to treatMetastatic non-small cell lung cancerRegimen in combination with: Pemetrexed (DB00642)•••••••••••••••••••••••
Used as adjunct in combination to treatMetastatic non-small cell lung cancerRegimen in combination with: Pemetrexed (DB00642)•••••••••••••••••••••••
Treatment ofMetastatic non-small cell lung cancer••••••••••••••••••••••• •••••••• •••••• ••••••••••••••••
Associated Therapies
Contraindications & Blackbox Warnings
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Pharmacodynamics

A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg.9

Mechanism of action

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs.9 As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity.8,7 Compared to wild-type EGFR, osimertinib has 200 times higher affinity for EGFR molecules with the L858R/T790M mutation in vitro.4,5

TargetActionsOrganism
AEpidermal growth factor receptor
inhibitor
regulator
Humans
Absorption

The median time to Cmax was found to be 6 hours.9

Volume of distribution

The mean volume of distribution at steady state is 918 L.9

Protein binding

Plasma protein binding of osimertinib is 95%.9

Metabolism

Osimertinib is metabolized to at least two pharmacologically active metabolites, AZ7550 and AZ5104, that circulate at approximately 10% of the concentration of the parent compound. Biochemical assays have shown that AZ7550 has similar potency and efficacy to osimertinib, while AZ5104 is more potent against mutant and wild-type EGFR. The main metabolic pathways are oxidation (predominantly by CYP3A) and dealkylation.9

Route of elimination

Osimertinib is primarily eliminated through excretion in the feces (68%), to a lesser extent through urine (14%), while only 2% is excreted unchanged.9

Half-life

The population estimated mean half-life is 48 hours.9

Clearance

Oral clearance is 14.3 L/hr.9

Adverse Effects
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Toxicity

Across clinical trials, interstitial lung disease (ILD)/pneumonitis occurred in 3.7% of treated patients with 0.3% of these being fatal. There is also a change of QTc interval prolongation; electrocardiogram and electrolytes should be monitored in patients with a history or predisposition for QTc prolongation. Cardiomyopathy occurred in 3% of patients, therefore left ventricular ejection fraction (LVEF) should be measured at baseline and during treatment. Osimertinib can cause embryo-fetal toxicity, requiring female patients to take effective birth control during therapy and for 6 weeks after final dose.9

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
AbametapirThe serum concentration of Osimertinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Osimertinib can be increased when combined with Abatacept.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Osimertinib.
AbrocitinibThe serum concentration of Osimertinib can be increased when it is combined with Abrocitinib.
AcalabrutinibThe metabolism of Osimertinib can be decreased when combined with Acalabrutinib.
Food Interactions
  • Avoid St. John's Wort. This herb induces the CYP3A metabolism of osimertinib, and therefore, dose adjustments are necessary if they must be co-administered.
  • Take at the same time every day.
  • Take with or without food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Osimertinib mesylateRDL94R2A161421373-66-1FUKSNUHSJBTCFJ-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TagrissoTablet, film coated80 mgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
TagrissoTablet, film coated40 mgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
TagrissoTablet40 mgOralAstra Zeneca2016-07-19Not applicableCanada flag
TagrissoTablet, film coated40 mgOralAstra Zeneca Ab2016-09-08Not applicableEU flag
TagrissoTablet, film coated40 mg/1OralAstraZeneca Pharmaceuticals LP2015-11-13Not applicableUS flag

Categories

ATC Codes
L01EB04 — Osimertinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as n-alkylindoles. These are compounds containing an indole moiety that carries an alkyl chain at the 1-position.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
N-alkylindoles
Direct Parent
N-alkylindoles
Alternative Parents
Aminophenyl ethers / Methoxyanilines / Indoles / Phenoxy compounds / Methoxybenzenes / Anisoles / Dialkylarylamines / Alkyl aryl ethers / Aminopyrimidines and derivatives / N-methylpyrroles
show 8 more
Substituents
Alkyl aryl ether / Amine / Aminophenyl ether / Aminopyrimidine / Aniline or substituted anilines / Anisole / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Carboximidic acid
show 27 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

UNII
3C06JJ0Z2O
CAS number
1421373-65-0
InChI Key
DUYJMQONPNNFPI-UHFFFAOYSA-N
InChI
InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)
IUPAC Name
N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
SMILES
COC1=C(NC2=NC=CC(=N2)C2=CN(C)C3=C2C=CC=C3)C=C(NC(=O)C=C)C(=C1)N(C)CCN(C)C

References

Synthesis Reference

Finlay MR, Anderton M, Ashton S, Ballard P, Bethel PA, Box MR, Bradbury RH, Brown SJ, Butterworth S, Campbell A, Chorley C, Colclough N, Cross DA, Currie GS, Grist M, Hassall L, Hill GB, James D, James M, Kemmitt P, Klinowska T, Lamont G, Lamont SG, Martin N, McFarland HL, Mellor MJ, Orme JP, Perkins D, Perkins P, Richmond G, Smith P, Ward RA, Waring MJ, Whittaker D, Wells S, Wrigley GL: Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J Med Chem. 2014 Oct 23;57(20):8249-67. doi: 10.1021/jm500973a. Epub 2014 Oct 1. Pubmed

General References
  1. Xu M, Xie Y, Ni S, Liu H: The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC). Ann Transl Med. 2015 May;3(7):96. doi: 10.3978/j.issn.2305-5839.2015.03.60. [Article]
  2. Tan CS, Gilligan D, Pacey S: Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer. Lancet Oncol. 2015 Sep;16(9):e447-59. doi: 10.1016/S1470-2045(15)00246-6. [Article]
  3. Ayeni D, Politi K, Goldberg SB: Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer. Clin Cancer Res. 2015 Sep 1;21(17):3818-20. doi: 10.1158/1078-0432.CCR-15-1211. Epub 2015 Jul 13. [Article]
  4. Yosaatmadja Y, Silva S, Dickson JM, Patterson AV, Smaill JB, Flanagan JU, McKeage MJ, Squire CJ: Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015 Dec;192(3):539-44. doi: 10.1016/j.jsb.2015.10.018. Epub 2015 Nov 2. [Article]
  5. Greig SL: Osimertinib: First Global Approval. Drugs. 2016 Feb;76(2):263-73. doi: 10.1007/s40265-015-0533-4. [Article]
  6. Shea M, Costa DB, Rangachari D: Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther Adv Respir Dis. 2016 Apr;10(2):113-29. doi: 10.1177/1753465815617871. Epub 2015 Nov 30. [Article]
  7. Liao BC, Lin CC, Yang JC: Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2015 Mar;27(2):94-101. doi: 10.1097/CCO.0000000000000164. [Article]
  8. Cross DA, Ashton SE, Ghiorghiu S, Eberlein C, Nebhan CA, Spitzler PJ, Orme JP, Finlay MR, Ward RA, Mellor MJ, Hughes G, Rahi A, Jacobs VN, Red Brewer M, Ichihara E, Sun J, Jin H, Ballard P, Al-Kadhimi K, Rowlinson R, Klinowska T, Richmond GH, Cantarini M, Kim DW, Ranson MR, Pao W: AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 2014 Sep;4(9):1046-61. doi: 10.1158/2159-8290.CD-14-0337. Epub 2014 Jun 3. [Article]
  9. FDA Approved Drug Products: TAGRISSO (osimertinib) tablets for oral use [Link]
  10. FDA Approved Drug Products: TAGRISSO (osimertinib) tablets, for oral use (February 2024) [Link]
Human Metabolome Database
HMDB0248778
PubChem Compound
71496458
PubChem Substance
310265210
ChemSpider
31042598
BindingDB
50029668
RxNav
1721560
ChEBI
90943
ChEMBL
CHEMBL3353410
ZINC
ZINC000098023177
PharmGKB
PA166131626
PDBe Ligand
YY3
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Osimertinib
PDB Entries
4zau / 6jwl / 6jx0 / 6jx4 / 6jxt / 6lud / 7jxm / 7jxp / 7jxw / 7k1h

Clinical Trials

Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package
PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableActive Not RecruitingNot AvailableNon-Small Cell Lung Cancer (NSCLC)1somestatusstop reasonjust information to hide
4Active Not RecruitingTreatmentNon-squamous Non-small-cell Lung Cancer (NSQ NSCLC)1somestatusstop reasonjust information to hide
4CompletedTreatmentNon-Small Cell Lung Cancer (NSCLC)1somestatusstop reasonjust information to hide
4RecruitingTreatmentAdenocarcinomas / Carcinoma / Non-Small Cell Lung Cancer (NSCLC)1somestatusstop reasonjust information to hide
4RecruitingTreatmentNon-Small Cell Lung Cancer (NSCLC)1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral40 mg
TabletOral40.000 mg
TabletOral80 mg
Tablet, film coatedOral
Tablet, film coatedOral40 mg/1
Tablet, film coatedOral80 mg/1
Tablet, film coatedOral40 mg
Tablet, film coatedOral80 mg
Tablet, coatedOral40 mg
Tablet, coatedOral80 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8946235No2015-02-032032-08-08US flag
US9732058No2017-08-152032-07-25US flag
US10183020No2019-01-222035-01-02US flag
US11524951No2012-07-252032-07-25US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0224 mg/mLALOGPS
logP4.47ALOGPS
logP4.49Chemaxon
logS-4.4ALOGPS
pKa (Strongest Acidic)13.64Chemaxon
pKa (Strongest Basic)8.87Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count7Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area87.55 Å2Chemaxon
Rotatable Bond Count10Chemaxon
Refractivity150.32 m3·mol-1Chemaxon
Polarizability56.84 Å3Chemaxon
Number of Rings4Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f6t-1000940000-881ac98115a67807e1c2
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0002-7009800000-261bd3bb771a787a5a9a
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0005-1000900000-0c69c2f1e82235236661
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00e9-7009210000-cf883a620bc54550c5d0
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-06r5-1001900000-6c90b48351349dcc0f86
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-01vk-1018900000-eb00242e73de11d1e619
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-222.40434
predicted
DeepCCS 1.0 (2019)
[M+H]+224.79991
predicted
DeepCCS 1.0 (2019)
[M+Na]+230.71243
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Regulator
General Function
Ubiquitin protein ligase binding
Specific Function
Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses. Known ligands include EGF, TG...
Gene Name
EGFR
Uniprot ID
P00533
Uniprot Name
Epidermal growth factor receptor
Molecular Weight
134276.185 Da
References
  1. Yosaatmadja Y, Silva S, Dickson JM, Patterson AV, Smaill JB, Flanagan JU, McKeage MJ, Squire CJ: Binding mode of the breakthrough inhibitor AZD9291 to epidermal growth factor receptor revealed. J Struct Biol. 2015 Dec;192(3):539-44. doi: 10.1016/j.jsb.2015.10.018. Epub 2015 Nov 2. [Article]
  2. Vasconcelos PENS, Gergis C, Viray H, Varkaris A, Fujii M, Rangachari D, VanderLaan PA, Kobayashi IS, Kobayashi SS, Costa DB: EGFR-A763_Y764insFQEA Is a Unique Exon 20 Insertion Mutation That Displays Sensitivity to Approved and In-Development Lung Cancer EGFR Tyrosine Kinase Inhibitors. JTO Clin Res Rep. 2020 Sep;1(3). doi: 10.1016/j.jtocrr.2020.100051. Epub 2020 May 13. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
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
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inducer
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. Osimertinib FDA label [File]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
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
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Xenobiotic-transporting atpase activity
Specific Function
High-capacity urate exporter functioning in both renal and extrarenal urate excretion. Plays a role in porphyrin homeostasis as it is able to mediates the export of protoporhyrin IX (PPIX) both fro...
Gene Name
ABCG2
Uniprot ID
Q9UNQ0
Uniprot Name
ATP-binding cassette sub-family G member 2
Molecular Weight
72313.47 Da

Drug created at November 18, 2015 17:23 / Updated at April 23, 2024 11:38