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Identification
NameErlotinib
Accession NumberDB00530  (APRD00951)
Typesmall molecule
Groupsapproved, investigational
Description

Erlotinib hydrochloride (trade name Tarceva, Genentech/OSIP, originally coded as OSI-774) is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer.

Similar to gefitinib, erlotinib specifically targets the epidermal growth factor receptor (EGFR) tyrosine kinase. It binds in a reversible fashion to the adenosine triphosphate (ATP) binding site of the receptor. Erlotinib has recently been shown to be a potent inhibitor of JAK2V617F activity. JAK2V617F is a mutant of tyrosine kinase JAK2, is found in most patients with polycythemia vera (PV) and a substantial proportion of patients with idiopathic myelofibrosis or essential thrombocythemia. The study suggests that erlotinib may be used for treatment of JAK2V617F-positive PV and other myeloproliferative disorders.

Structure
Thumb
Synonyms
SynonymLanguageCode
OSI-774Not AvailableNot Available
Salts
Name/CAS Structure Properties
Erlotinib Hydrochloride
183319-69-9
Thumb
  • InChI Key: GTTBEUCJPZQMDZ-UHFFFAOYSA-N
  • Monoisotopic Mass: 429.145533978
  • Average Mass: 429.897
DBSALT000064
Brand names
NameCompany
TarcevaGenetech
Brand mixturesNot Available
Categories
CAS number183321-74-6
WeightAverage: 393.4357
Monoisotopic: 393.168856239
Chemical FormulaC22H23N3O4
InChI KeyAAKJLRGGTJKAMG-UHFFFAOYSA-N
InChI
InChI=1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
IUPAC Name
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
SMILES
COCCOC1=C(OCCOC)C=C2C(NC3=CC=CC(=C3)C#C)=NC=NC2=C1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassNaphthyridines
SubclassQuinazolines
Direct parentQuinazolinamines
Alternative parentsPhenol Ethers; Alkyl Aryl Ethers; Aminopyrimidines and Derivatives; Polyamines; Secondary Amines
Substituentsphenol ether; aminopyrimidine; alkyl aryl ether; benzene; pyrimidine; polyamine; secondary amine; ether; amine; organonitrogen compound
Classification descriptionThis compound belongs to the quinazolinamines. These are heterocyclic aromatic compounds containing a quianazoline moiety substituted by one or more amine groups.
Pharmacology
IndicationFor the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Also for use, in combination with gemcitabine, as the first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer.
PharmacodynamicsNot Available
Mechanism of actionThe mechanism of clinical antitumor action of erlotinib is not fully characterized. Erlotinib inhibits the intracellular phosphorylation of tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Specificity of inhibition with regard to other tyrosine kinase receptors has not been fully characterized. EGFR is expressed on the cell surface of normal cells and cancer cells.
AbsorptionErlotinib is about 60% absorbed after oral administration and its bioavailability is substantially increased by food to almost 100%. Peak plasma levels occur 4 hours after dosing. The solubility of erlotinib is pH dependent. Solubility decreases pH increases. Smoking also decrease the exposure of erlotinib.
Volume of distribution

Apparent volume of distribution = 232 L

Protein binding93% protein bound to albumin and alpha-1 acid glycoprotein (AAG)
Metabolism

Metabolism occurs in the liver. In vitro assays of cytochrome P450 metabolism showed that erlotinib is metabolized primarily by CYP3A4 and to a lesser extent by CYP1A2, and the extrahepatic isoform CYP1A1.

Route of eliminationFollowing a 100 mg oral dose, 91% of the dose was recovered in which 83% was in feces (1% of the dose as unchanged parent compound) and 8% in urine (0.3% of the dose as unchanged parent compound).
Half lifeMedian half-life of 36.2 hours.
Clearance

Smokers have a 24% higher rate of erlotinib clearance.

ToxicitySymptoms of overdose include diarrhea, rash, and liver transaminase elevation. The most common adverse reactions (>50%) in NSCLC are rash, diarrhea, anorexia and fatigue. The most common adverse reactions (>50%) in pancreatic cancer are fatigue, rash, nausea and anorexia.
Affected organisms
  • Humans and other mammals
Pathways
PathwayCategorySMPDB ID
Erlotinib Action PathwayDrug actionSMP00472
SNP Mediated Effects
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeEffectReference(s)
Epidermal growth factor receptor
Gene symbol: EGFR
UniProt: P00533
Not AvailableG719A/C OR (L858R and L861Q)Not AvailableAssociated with enhanced activation of the EGFR tyrosine kinase in patients with non-small cell lung cancer (NSCLC) recieving tyrosine kinase inhibitor therapy.15118073
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9359
Blood Brain Barrier + 0.9376
Caco-2 permeable + 0.5737
P-glycoprotein substrate Substrate 0.5982
P-glycoprotein inhibitor I Inhibitor 0.5958
P-glycoprotein inhibitor II Non-inhibitor 0.6169
Renal organic cation transporter Non-inhibitor 0.7171
CYP450 2C9 substrate Non-substrate 0.7942
CYP450 2D6 substrate Non-substrate 0.7611
CYP450 3A4 substrate Substrate 0.5886
CYP450 1A2 substrate Inhibitor 0.7826
CYP450 2C9 substrate Non-inhibitor 0.5739
CYP450 2D6 substrate Non-inhibitor 0.6329
CYP450 2C19 substrate Inhibitor 0.598
CYP450 3A4 substrate Inhibitor 0.7194
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.7911
Ames test AMES toxic 0.5195
Carcinogenicity Non-carcinogens 0.9551
Biodegradation Not ready biodegradable 0.9907
Rat acute toxicity 2.3958 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8158
hERG inhibition (predictor II) Non-inhibitor 0.6776
Pharmacoeconomics
Manufacturers
  • Osi pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
TabletOral25 mg, 100 mg, 150 mg
Prices
Unit descriptionCostUnit
Tarceva 150 mg tablet163.98USDtablet
Tarceva 100 mg tablet144.98USDtablet
Tarceva 25 mg tablet52.78USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States69002212000-11-092020-11-09
United States57474981998-11-082018-11-08
Canada25149772010-06-222024-02-11
Canada22167962003-09-022015-06-06
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilityVery slightly soluble (hydrochloride salt - maximal solubility of approximately 0.4 mg/mL occurs at a pH of approximately 2)Not Available
logP2.7Not Available
Predicted Properties
PropertyValueSource
water solubility8.91e-03 g/lALOGPS
logP3.13ALOGPS
logP3.2ChemAxon
logS-4.6ALOGPS
pKa (strongest acidic)16.14ChemAxon
pKa (strongest basic)4.59ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count7ChemAxon
hydrogen donor count1ChemAxon
polar surface area74.73ChemAxon
rotatable bond count10ChemAxon
refractivity107.79ChemAxon
polarizability43.48ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterYesChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US5747498
General Reference
  1. Raymond E, Faivre S, Armand JP: Epidermal growth factor receptor tyrosine kinase as a target for anticancer therapy. Drugs. 2000;60 Suppl 1:15-23; discussion 41-2. Pubmed
  2. Li Z, Xu M, Xing S, Ho WT, Ishii T, Li Q, Fu X, Zhao ZJ: Erlotinib effectively inhibits JAK2V617F activity and polycythemia vera cell growth. J Biol Chem. 2007 Feb 9;282(6):3428-32. Epub 2006 Dec 18. Pubmed
  3. Dudek AZ, Kmak KL, Koopmeiners J, Keshtgarpour M: Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer. Lung Cancer. 2006 Jan;51(1):89-96. Epub 2005 Nov 14. Pubmed
  4. Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI: Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer. 2004 Dec;11(4):793-814. Pubmed
  5. Blum G, Gazit A, Levitzki A: Substrate competitive inhibitors of IGF-1 receptor kinase. Biochemistry. 2000 Dec 26;39(51):15705-12. Pubmed
External Links
ResourceLink
KEGG DrugD07907
PubChem Compound176870
PubChem Substance46508021
ChemSpider154044
BindingDB5446
ChEBI114785
ChEMBLCHEMBL553
Therapeutic Targets DatabaseDAP001010
PharmGKBPA134687924
HETAQ4
Drug Product Database2269023
RxListhttp://www.rxlist.com/cgi/generic4/tarceva.htm
Drugs.comhttp://www.drugs.com/cdi/erlotinib.html
WikipediaErlotinib
ATC CodesL01XE03
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelshow(999 KB)
MSDSshow(107 KB)
Interactions
Drug Interactions
Drug
AtazanavirThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
ClarithromycinThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
ErythromycinThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
IndinavirThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
ItraconazoleItraconazole may decrease the metabolism of erlotinib. Monitor for changes in the therapeutic and adverse effects of erlotinib if itraconazole is initiated, discontinued or dose changed.
KetoconazoleThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
NefazodoneThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
NelfinavirThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
RifabutinDecreased levels/effect of erlotinib
RifampicinDecreased levels/effect of erlotinib
RifapentineDecreased levels/effect of erlotinib
RitonavirThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
SaquinavirThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
St. John's WortDecreased levels/effect of erlotinib
TelithromycinTelithromycin may reduce clearance of Erlotinib. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Erlotinib if Telithromycin is initiated, discontinued or dose changed.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
TroleandomycinThis CYP3A4 inhibitor increases levels/toxicity of erlotinib
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of erlotinib by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of erlotinib if voriconazole is initiated, discontinued or dose changed.
Food Interactions
  • Take at least 1 hour before or 2 hours after any food.
  • Take with a glass of water.

Targets

1. Epidermal growth factor receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: antagonist

Components

Name UniProt ID Details
Epidermal growth factor receptor P00533 Details

References:

  1. Kim TE, Murren JR: Erlotinib OSI/Roche/Genentech. Curr Opin Investig Drugs. 2002 Sep;3(9):1385-95. Pubmed
  2. Laird AD, Cherrington JM: Small molecule tyrosine kinase inhibitors: clinical development of anticancer agents. Expert Opin Investig Drugs. 2003 Jan;12(1):51-64. Pubmed
  3. Delbaldo C, Faivre S, Raymond E: [Epidermal growth factor inhibitors] Rev Med Interne. 2003 Jun;24(6):372-83. Pubmed
  4. Bulgaru AM, Mani S, Goel S, Perez-Soler R: Erlotinib (Tarceva): a promising drug targeting epidermal growth factor receptor tyrosine kinase. Expert Rev Anticancer Ther. 2003 Jun;3(3):269-79. Pubmed
  5. Akita RW, Sliwkowski MX: Preclinical studies with Erlotinib (Tarceva). Semin Oncol. 2003 Jun;30(3 Suppl 7):15-24. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Nuclear receptor subfamily 1 group I member 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Nuclear receptor subfamily 1 group I member 2 O75469 Details

References:

  1. Harmsen S, Meijerman I, Beijnen JH, Schellens JH: Nuclear receptor mediated induction of cytochrome P450 3A4 by anticancer drugs: a key role for the pregnane X receptor. Cancer Chemother Pharmacol. 2009 Jun;64(1):35-43. Epub 2008 Oct 7. Pubmed
  2. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J, Hsieh LS, Chidambaram N, Zimmerman P, Pazdur R: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res. 2005 Sep 15;11(18):6414-21. Pubmed
  3. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed
  4. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ: Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. Pubmed

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed

3. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Lu JF, Eppler SM, Wolf J, Hamilton M, Rakhit A, Bruno R, Lum BL: Clinical pharmacokinetics of erlotinib in patients with solid tumors and exposure-safety relationship in patients with non-small cell lung cancer. Clin Pharmacol Ther. 2006 Aug;80(2):136-45. Pubmed
  3. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J, Hsieh LS, Chidambaram N, Zimmerman P, Pazdur R: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res. 2005 Sep 15;11(18):6414-21. Pubmed
  4. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed
  5. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ: Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. Pubmed

4. Cytochrome P450 1A1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A1 P04798 Details

References:

  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Johnson JR, Cohen M, Sridhara R, Chen YF, Williams GM, Duan J, Gobburu J, Booth B, Benson K, Leighton J, Hsieh LS, Chidambaram N, Zimmerman P, Pazdur R: Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res. 2005 Sep 15;11(18):6414-21. Pubmed
  3. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed

5. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed

6. Cytochrome P450 2C8

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2C8 P10632 Details

References:

  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Hamilton M, Wolf JL, Rusk J, Beard SE, Clark GM, Witt K, Cagnoni PJ: Effects of smoking on the pharmacokinetics of erlotinib. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2166-71. Pubmed

7. Cytochrome P450 1B1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1B1 Q16678 Details

References:

  1. van Erp NP, Gelderblom H, Guchelaar HJ: Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev. 2009 Dec;35(8):692-706. Epub 2009 Sep 5. Pubmed
  2. Li J, Zhao M, He P, Hidalgo M, Baker SD: Differential metabolism of gefitinib and erlotinib by human cytochrome P450 enzymes. Clin Cancer Res. 2007 Jun 15;13(12):3731-7. Pubmed

8. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Liu Y, Ramirez J, House L, Ratain MJ: The UGT1A1*28 polymorphism correlates with erlotinib’s effect on SN-38 glucuronidation. Eur J Cancer. 2010 Jul;46(11):2097-103. doi: 10.1016/j.ejca.2010.04.022. Epub 2010 May 23. Pubmed

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label

2. Alpha-1-acid glycoprotein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Alpha-1-acid glycoprotein 1 P02763 Details

References:

  1. FDA label

Transporters

1. ATP-binding cassette sub-family G member 2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
ATP-binding cassette sub-family G member 2 Q9UNQ0 Details

References:

  1. Noguchi K, Kawahara H, Kaji A, Katayama K, Mitsuhashi J, Sugimoto Y: Substrate-dependent bidirectional modulation of P-glycoprotein-mediated drug resistance by erlotinib. Cancer Sci. 2009 Sep;100(9):1701-7. Epub 2009 May 12. Pubmed

2. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Marchetti S, de Vries NA, Buckle T, Bolijn MJ, van Eijndhoven MA, Beijnen JH, Mazzanti R, van Tellingen O, Schellens JH: Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1-/-/Mdr1a/1b-/- (triple-knockout) and wild-type mice. Mol Cancer Ther. 2008 Aug;7(8):2280-7. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:23