Identification

Name
Alectinib
Accession Number
DB11363
Description

Alectinib is a second generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. It is specifically used in the treatment of non-small cell lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability.

Approved under accelerated approval in 2015, alectinib is indicated for use in patients who have progressed on or were not tolerant of crizotinib, which is associated with the development of resistance.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 482.6166
Monoisotopic: 482.268176352
Chemical Formula
C30H34N4O2
Synonyms
  • 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
  • Alectinib
External IDs
  • AF 802
  • AF-802
  • AF802
  • CH 5424802
  • CH-5424802
  • CH5424802
  • RO-5424802
  • RO5424802

Pharmacology

Indication

Alectinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics
Not Available
Mechanism of action

Alectinib is a second generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. It is specifically used in the treatment of non-small cell lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumour cell viability. Both alectinib and its major active metabolite M4 demonstrate similar in vivo and in vitro activity against multiple mutant forms of ALK.

TargetActionsOrganism
AALK tyrosine kinase receptor
inhibitor
Humans
Absorption

Alectinib reached maximal concentrations at 4 hours following administration of 600 mg twice daily under fed conditions in patients with ALK-positive NSCLC. The absolute bioavailability was 37% in the fed state. A high-fat, high-calorie meal increased the combined exposure of alectinib and its major metabolite M4 by 3.1-fold following oral administration of a single 600 mg dose.

Volume of distribution

4016 L

Protein binding

Alectinib and its major metabolite M4 are >99% bound to human plasma proteins.

Metabolism

Alectinib is metabolized by CYP3A4 to its major active metabolite M4. M4 is then further metabolized by CYP3A4. Both alectinib and M4 demonstrate similar in vivo and in vitro activity. In vitro studies suggest that alectinib is not a substrate for P-gp while M4 is.

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Route of elimination

When radioactively labeled, 98% of radioactivity was found in feces with 84% of that amount excreted as unchanged alectinib and 6% as M4. Less than 0.5% was found to be recovered in urine.

Half-life

The mean elimination half life is 33 hr for alectinib and 31 hr for M4.

Clearance

The apparent clearance is 81.9L/hr for alectinib and 217 L/hr for M4.

Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

The most common adverse reactions (>5%) associated with alectinib use were fatigue, constipation, edema, and myalgia. Less common effects associated with use were hepatotoxicity, interstitial lung disease (ILD)/pneumonitis, bradycardia, severe myalgia and creatine phosphokinase (CPK) elevation, and embryo-fetal toxicity. Females of reproductive potential are advised to use effective contraception during treatment with alectinib and for 1 week following the final dose.

Affected organisms
Not Available
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
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Alectinib.
AbametapirThe metabolism of Alectinib can be decreased when combined with Abametapir.
AbataceptThe metabolism of Alectinib can be increased when combined with Abatacept.
AbemaciclibAlectinib may decrease the excretion rate of Abemaciclib which could result in a higher serum level.
AcalabrutinibThe metabolism of Alectinib can be decreased when combined with Acalabrutinib.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Alectinib.
AcetazolamideThe metabolism of Alectinib can be decreased when combined with Acetazolamide.
AdalimumabThe metabolism of Alectinib can be increased when combined with Adalimumab.
AfatinibAlectinib may decrease the excretion rate of Afatinib which could result in a higher serum level.
AlbendazoleThe metabolism of Alectinib can be decreased when combined with Albendazole.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
  • Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of alectinib.
  • Exercise caution with St. John's Wort. This herb induces CYP3A metabolism, which may reduce serum levels of alectinib.
  • Take with food.

Products

Product Ingredients
IngredientUNIICASInChI Key
Alectinib hydrochlorideP9YY73LO6J1256589-74-8GYABBVHSRIHYJR-UHFFFAOYSA-N
International/Other Brands
Alecensa
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AlecensaCapsule150 mg/1OralGenentech, Inc.2015-12-11Not applicableUS flag
AlecensaroCapsuleOralHoffmann La Roche2016-10-14Not applicableCanada flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01XE36 — Alectinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as carbazoles. These are compounds containing a three ring system containing a pyrrole ring fused on either side to a benzene ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Indoles and derivatives
Sub Class
Carbazoles
Direct Parent
Carbazoles
Alternative Parents
Naphthalenes / Indoles / Aryl ketones / Dialkylarylamines / Aminopiperidines / Morpholines / Vinylogous amides / Heteroaromatic compounds / Pyrroles / Trialkylamines
show 7 more
Substituents
4-aminopiperidine / Amine / Aromatic heteropolycyclic compound / Aryl ketone / Azacycle / Benzenoid / Carbazole / Carbonitrile / Dialkyl ether / Dialkylarylamine
show 22 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
Not Available

Chemical Identifiers

UNII
LIJ4CT1Z3Y
CAS number
1256580-46-7
InChI Key
KDGFLJKFZUIJMX-UHFFFAOYSA-N
InChI
InChI=1S/C30H34N4O2/c1-4-20-16-23-24(17-26(20)34-9-7-21(8-10-34)33-11-13-36-14-12-33)30(2,3)29-27(28(23)35)22-6-5-19(18-31)15-25(22)32-29/h5-6,15-17,21,32H,4,7-14H2,1-3H3
IUPAC Name
9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-5H,6H,11H-benzo[b]carbazole-3-carbonitrile
SMILES
CCC1=CC2=C(C=C1N1CCC(CC1)N1CCOCC1)C(C)(C)C1=C(C3=CC=C(C=C3N1)C#N)C2=O

References

General References
  1. McKeage K: Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer. Drugs. 2015 Jan;75(1):75-82. doi: 10.1007/s40265-014-0329-y. [PubMed:25428710]
  2. Sakamoto H, Tsukaguchi T, Hiroshima S, Kodama T, Kobayashi T, Fukami TA, Oikawa N, Tsukuda T, Ishii N, Aoki Y: CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant. Cancer Cell. 2011 May 17;19(5):679-90. doi: 10.1016/j.ccr.2011.04.004. [PubMed:21575866]
  3. Kodama T, Tsukaguchi T, Yoshida M, Kondoh O, Sakamoto H: Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance. Cancer Lett. 2014 Sep 1;351(2):215-21. doi: 10.1016/j.canlet.2014.05.020. Epub 2014 Jun 2. [PubMed:24887559]
  4. Sullivan I, Planchard D: ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. Ther Adv Med Oncol. 2016 Jan;8(1):32-47. doi: 10.1177/1758834015617355. [PubMed:26753004]
KEGG Drug
D10542
PubChem Compound
49806720
PubChem Substance
310265230
ChemSpider
26326738
BindingDB
50362781
RxNav
1727455
ChEBI
90936
ChEMBL
CHEMBL1738797
ZINC
ZINC000066166864
PharmGKB
PA166160050
PDBe Ligand
EMH
RxList
RxList Drug Page
Wikipedia
Alectinib
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
3aox / 5xv7
FDA label
Download (581 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentAnaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer1
3Active Not RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
3CompletedTreatmentAnaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer / Non-Small Cell Lung Carcinoma (NSCLC)1
3RecruitingTreatmentALK+ Advanced NSCLC1
3RecruitingTreatmentNeoplasms1
3RecruitingTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2Active Not RecruitingTreatmentBiliary Cancer / Cancer, Bladder / Neoplasms / Salivary Cancer / Tumors, Solid1
2CompletedTreatmentNon-Small Cell Lung Carcinoma (NSCLC)1
2Not Yet RecruitingTreatmentMalignancies / Neoplasms / Tumors1
2Not Yet RecruitingTreatmentRare Tumor1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral150 mg/1
CapsuleOral150 MG
Capsule, coatedOral150 mg
CapsuleOral
Capsule150 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9126931No2015-09-082031-05-29US flag
US9440922No2016-09-132030-06-09US flag
US9365514No2016-06-142032-03-04US flag
US10350214No2019-07-162035-04-24US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
pKa7.05FDA Label
Predicted Properties
PropertyValueSource
Water Solubility0.0105 mg/mLALOGPS
logP5.59ALOGPS
logP4.89ChemAxon
logS-4.7ALOGPS
pKa (Strongest Acidic)12.18ChemAxon
pKa (Strongest Basic)7.59ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area72.36 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity155.11 m3·mol-1ChemAxon
Polarizability56.56 Å3ChemAxon
Number of Rings6ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Transmembrane receptor protein tyrosine kinase activity
Specific Function
Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis a...
Gene Name
ALK
Uniprot ID
Q9UM73
Uniprot Name
ALK tyrosine kinase receptor
Molecular Weight
176440.535 Da

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
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
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
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

Drug created on January 19, 2016 12:11 / Updated on September 20, 2020 08:50

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