Identification
- Name
- Alectinib
- Accession Number
- DB11363
- Type
- Small Molecule
- Groups
- Approved, Investigational
- 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.
- Structure
Structure for Alectinib (DB11363)
- 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
- Product Ingredients
Ingredient UNII CAS InChI Key Alectinib hydrochloride P9YY73LO6J 1256589-74-8 GYABBVHSRIHYJR-UHFFFAOYSA-N - Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Unlock Additional DataAlecensa Capsule 150 mg/1 Oral Genentech, Inc. 2015-12-11 Not applicable US 
Alecensaro Capsule Oral Hoffmann La Roche 2016-10-14 Not applicable Canada 
Additional Data Available- Application NumberApplication Number
A unique ID assigned by the FDA when a product is submitted for approval by the labeller.
Learn more - Product CodeProduct Code
A governmentally-recognized ID which uniquely identifies the product within its regulatory market.
Learn more
- International/Other Brands
- Alecensa
- Categories
- Antineoplastic Agents
- Antineoplastic and Immunomodulating Agents
- BCRP/ABCG2 Inhibitors
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Indoles
- Kinase Inhibitor
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- Protein Kinase Inhibitors
- Tyrosine Kinase Inhibitors
- UNII
- LIJ4CT1Z3Y
- CAS number
- 1256580-46-7
- Weight
- Average: 482.6166
Monoisotopic: 482.268176352 - Chemical Formula
- C30H34N4O2
- 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
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
- 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.
Target Actions Organism AALK tyrosine kinase receptor inhibitorHumans - 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.
- 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.
- 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
Comprehensive structured data on known drug adverse effects with statistical prevalence. MedDRA and ICD10 ids are provided for adverse effect conditions and symptoms.
Learn moreStructured data covering drug contraindications. Each contraindication describes a scenario in which the drug is not to be used. Includes restrictions on co-administration, contraindicated populations, and more.
Learn moreStructured data representing warnings from the black box section of drug labels. These warnings cover important and dangerous risks, contraindications, or adverse effects.
Learn moreInteractions
- 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.
Drug Interaction Unlock Additional Data3,5-diiodothyropropionic acid The therapeutic efficacy of 3,5-diiodothyropropionic acid can be decreased when used in combination with Alectinib. 3,5-Diiodotyrosine The therapeutic efficacy of 3,5-Diiodotyrosine can be decreased when used in combination with Alectinib. 6-Deoxyerythronolide B The metabolism of Alectinib can be decreased when combined with 6-Deoxyerythronolide B. 7-ethyl-10-hydroxycamptothecin The metabolism of Alectinib can be decreased when combined with 7-ethyl-10-hydroxycamptothecin. 9-aminocamptothecin The metabolism of Alectinib can be decreased when combined with 9-aminocamptothecin. Abaloparatide The therapeutic efficacy of Abaloparatide can be decreased when used in combination with Alectinib. Abatacept The metabolism of Alectinib can be increased when combined with Abatacept. Abemaciclib Alectinib may decrease the excretion rate of Abemaciclib which could result in a higher serum level. Acalabrutinib The metabolism of Alectinib can be decreased when combined with Acalabrutinib. Acetaminophen The metabolism of Acetaminophen can be increased when combined with Alectinib. Additional Data Available- Extended DescriptionExtended Description
Extended description of the mechanism of action and particular properties of each drug interaction.
Learn more - Severity
- Evidence Level
- ActionAction
An effect category for each drug interaction. Know how this interaction affects the subject drug.
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- Food Interactions
- Take with food.
References
- General References
- 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]
- 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]
- 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]
- 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]
- External Links
- 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
- ATC Codes
- L01XE36 — Alectinib
- AHFS Codes
- 10:00.00 — Antineoplastic Agents
- PDB Entries
- 3aox / 5xv7
- FDA label
- Download (581 KB)
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 150 mg/1 Capsule Oral - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Unlock Additional DataUS9126931 No 2015-09-08 2031-05-29 US US9440922 No 2016-09-13 2030-06-09 US US9365514 No 2016-06-14 2032-03-04 US US10350214 No 2015-04-24 2035-04-24 US Additional Data Available- Filed On
Properties
- State
- Solid
- Experimental Properties
Property Value Source pKa 7.05 FDA Label - Predicted Properties
Property Value Source Water Solubility 0.0105 mg/mL ALOGPS logP 5.59 ALOGPS logP 4.89 ChemAxon logS -4.7 ALOGPS pKa (Strongest Acidic) 12.18 ChemAxon pKa (Strongest Basic) 7.59 ChemAxon Physiological Charge 1 ChemAxon Hydrogen Acceptor Count 5 ChemAxon Hydrogen Donor Count 1 ChemAxon Polar Surface Area 72.36 Å2 ChemAxon Rotatable Bond Count 3 ChemAxon Refractivity 155.11 m3·mol-1 ChemAxon Polarizability 56.56 Å3 ChemAxon Number of Rings 6 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Taxonomy
- 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
- Carbazole / Naphthalene / Indole / Tertiary aliphatic/aromatic amine / Dialkylarylamine / Aryl ketone / 4-aminopiperidine / Morpholine / Oxazinane / Piperidine show 22 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not 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
- SubstrateInhibitor
- 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 May 28, 2020 00:58
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