Identification

Name
Alectinib
Accession Number
DB11363
Type
Small Molecule
Groups
Approved
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
Thumb
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
IngredientUNIICASInChI Key
Alectinib hydrochlorideP9YY73LO6J1256589-74-8GYABBVHSRIHYJR-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AlecensaCapsule150 mg/1OralGenentech, Inc.2015-12-11Not applicableUs
AlecensaroCapsule150 mgOralHoffmann La Roche2016-10-14Not applicableCanada
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.

Structured Indications
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
Human
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
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Alectinib.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Alectinib.Experimental
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Alectinib.Approved
BevacizumabBevacizumab may increase the cardiotoxic activities of Alectinib.Approved, Investigational
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Alectinib.Approved
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Alectinib.Approved
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Alectinib.Approved
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Alectinib.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Alectinib.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Alectinib.Experimental
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Alectinib.Approved
DeslanosideDeslanoside may decrease the cardiotoxic activities of Alectinib.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Alectinib.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Alectinib.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Alectinib.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Alectinib.Approved, Investigational
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Alectinib.Approved, Investigational
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Alectinib.Approved
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Alectinib.Approved
GitoformateGitoformate may decrease the cardiotoxic activities of Alectinib.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Alectinib.Experimental
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Alectinib.Approved
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Alectinib.Experimental
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Alectinib.Approved
OleandrinOleandrin may decrease the cardiotoxic activities of Alectinib.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Alectinib.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Alectinib.Approved, Vet Approved
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Alectinib.Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Alectinib.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Alectinib.Experimental
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Alectinib.Approved
RanolazineThe serum concentration of Ranolazine can be increased when it is combined with Alectinib.Approved, Investigational
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Alectinib.Approved, Investigational
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Alectinib.Approved
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Alectinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Alectinib.Approved, Investigational
VincristineThe serum concentration of Vincristine can be increased when it is combined with Alectinib.Approved, Investigational
Food Interactions
Not Available

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]
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
FDA label
Download (581 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Non-Squamous Non-Small Cell Lung Cancer1
1CompletedNot AvailableHealthy Volunteers1
1CompletedTreatmentHealthy Volunteers3
1CompletedTreatmentHepatic Impairment1
1Unknown StatusTreatmentALK-Rearranged Non-Small Cell Lung Cancer1
1, 2Not Yet RecruitingTreatmentGlioblastoma, Adult1
1, 2RecruitingTreatmentALK-positive Non-small Cell Lung Cancer (NSCLC) / RET-positive Non-small Cell Lung Cancer (NSCLC) / RET-positive Thyroid Cancer1
1, 2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)2
2RecruitingTreatmentNeoplasms1
2, 3RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
3Active Not RecruitingTreatmentAnaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer1
3Active Not RecruitingTreatmentAnaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer / Lung Cancer Non-Small Cell Cancer (NSCLC)1
3Active Not RecruitingTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
3RecruitingTreatmentNeoplasms1
Not AvailableNo Longer AvailableNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)1
Not AvailableNot Yet RecruitingNot AvailableLung Cancer Non-Small Cell Cancer (NSCLC)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CapsuleOral150 mg/1
CapsuleOral150 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US9126931No2011-05-292031-05-29Us
US9440922No2010-06-092030-06-09Us
US9365514No2012-03-042032-03-04Us

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)6.97ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area72.36 Å2ChemAxon
Rotatable Bond Count3ChemAxon
Refractivity155.11 m3·mol-1ChemAxon
Polarizability56.45 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

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 December 11, 2017 13:02