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
- 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 Alecensa Capsule 150 mg/1 Oral Genentech, Inc. 2015-12-11 Not applicable US 
Alecensaro Capsule 150 mg Oral Hoffmann La Roche 2016-10-14 Not applicable Canada 
- Categories
- UNII
- LIJ4CT1Z3Y
- CAS number
- Not Available
- 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=C(N1)C=C(C=C3)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 inhibitorHuman - 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
Interactions
- Drug Interactions
Drug Interaction Acebutolol The serum concentration of Acebutolol can be increased when it is combined with Alectinib. Acetyldigitoxin Acetyldigitoxin may decrease the cardiotoxic activities of Alectinib. Acetyldigoxin Acetyldigoxin may decrease the cardiotoxic activities of Alectinib. Acetylsalicylic acid The serum concentration of Acetylsalicylic acid can be increased when it is combined with Alectinib. Afatinib The serum concentration of Afatinib can be increased when it is combined with Alectinib. Alitretinoin The serum concentration of Alitretinoin can be increased when it is combined with Alectinib. Amitriptyline The serum concentration of Amitriptyline can be increased when it is combined with Alectinib. Ancestim The risk or severity of cytotoxicity can be increased when Ancestim is combined with Alectinib. Ascorbic acid The serum concentration of Ascorbic acid can be increased when it is combined with Alectinib. Betamethasone The serum concentration of Betamethasone can be increased when it is combined with Alectinib. - Food Interactions
- Not Available
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
- D10450
- PubChem Compound
- 49806720
- PubChem Substance
- 310265230
- ChemSpider
- 26326738
- BindingDB
- 50362781
- ChEBI
- 90936
- ChEMBL
- CHEMBL1738797
- PharmGKB
- PA166160050
- HET
- 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
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage forms
Form Route Strength Capsule Oral 150 mg/1 Capsule Oral 150 mg - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) US9126931 No 2011-05-29 2031-05-29 US US9440922 No 2010-06-09 2030-06-09 US US9365514 No 2012-03-04 2032-03-04 US
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) 6.97 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 56.45 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
- Human
- 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
Carriers
- Kind
- Protein
- Organism
- Human
- Pharmacological action
- No
- 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
Transporters
- Kind
- Protein
- Organism
- Human
- 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
Drug created on January 19, 2016 12:11 / Updated on October 16, 2018 08:43