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Breakthrough therapy
Alectinib
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    Alectinib

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    Alectinib
    Alectinib structure.svg
    Clinical data
    Pronunciation /əˈlɛktɪnɪb/ ə-LEK-ti-nib
    Trade names Alecensa
    AHFS/Drugs.com Monograph
    MedlinePlus a616007
    License data
    Pregnancy
    category
    • AU: D
    Routes of
    administration    		 By mouth
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    • EU: Rx-only
    Pharmacokinetic data
    Bioavailability 37% (under fed conditions)
    Protein binding >99%
    Metabolism Mainly CYP3A4
    Metabolites M4 (active)
    Elimination half-life 33 hours (alectinib), 31 hours (M4)
    Excretion Feces (98%)
    Identifiers
    • 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    CompTox Dashboard (EPA)
    ECHA InfoCard 100.256.083
    Chemical and physical data
    Formula C30H34N4O2
    Molar mass 482.628 g·mol−1
    3D model (JSmol)
    • CCc1cc2c(cc1N3CCC(CC3)N4CCOCC4)C(c5c(c6ccc(cc6[nH]5)C#N)C2=O)(C)C
    • 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 COPY
    • Key:KDGFLJKFZUIJMX-UHFFFAOYSA-N

    Alectinib (INN,), sold under the brand name Alecensa, is a medication that is used to treat non-small-cell lung cancer (NSCLC). It blocks the activity of anaplastic lymphoma kinase (ALK). It is taken by mouth. It was developed by Chugai Pharmaceutical Co. Japan, which is part of the Hoffmann-La Roche group.

    History, clinical trials, Approvals and medical uses

    Alectinib was approved in Japan in July 2014, for the treatment of ALK fusion-gene positive, unresectable, advanced or recurrent non-small-cell lung cancer (NSCLC).

    It was granted an accelerated approval by the US Food and Drug Administration (FDA) in December 2015, to treat people with advanced ALK-positive NSCLC whose disease worsened after, or who could not tolerate, treatment with crizotinib (Xalkori).

    It received conditional approval by the European Medicines Agency in February 2017, for the same indication.

    The approvals were based mainly on two trials: In a Japanese Phase I–II trial, after approximately 2 years, 19.6% of patients had achieved a complete response, and the 2-year progression-free survival rate was 76%. In February 2016 the J-ALEX phase III study comparing alectinib with crizotinib was terminated early because an interim analysis showed that progression-free survival was longer with alectinib.

    In November 2017, the FDA approved alectinib for the first-line treatment of people with ALK-positive metastatic non-small cell lung cancer. This based on the phase 3 ALEX trial comparing it with crizotinib.

    Contraindications

    There are no reported contraindications.

    Side effects

    Apart from unspecific gastrointestinal effects such as constipation (in 34% of patients) and nausea (22%), common adverse effects in studies included oedema (swelling; 34%), myalgia (muscle pain; 31%), anaemia (low red blood cell count), sight disorders, light sensitivity and rashes (all below 20%). Serious side effects occurred in 19% of patients; fatal ones in 2.8%.

    Interactions

    Alectinib has a low potential for interactions. While it is metabolised by the liver enzyme CYP3A4, and blockers of this enzyme accordingly increase its concentrations in the body, they also decrease concentrations of the active metabolite M4, resulting in only a small overall effect. Conversely, CYP3A4 inducers decrease alectinib concentrations and increase M4 concentrations. Interactions via other CYP enzymes and transporter proteins cannot be excluded but are unlikely to be of clinical significance.

    Pharmacology

    Mechanism of action

    The substance potently and selectively blocks two receptor tyrosine kinase enzymes: anaplastic lymphoma kinase (ALK) and the RET proto-oncogene. The active metabolite M4 has similar activity against ALK. Inhibition of ALK subsequently blocks cell signalling pathways, including STAT3 and the PI3K/AKT/mTOR pathway, and induces death (apoptosis) of tumour cells.

    Pharmacokinetics

    Proposed metabolism of alectinib. Alectinib itself and the active metabolite M4 are the main compounds found in the circulation, while the others are minor metabolites.

    When taken with a meal, the absolute bioavailability of the drug is 37%, and highest blood plasma concentrations are reached after four to six hours. Steady state conditions are reached within seven days. Plasma protein binding of alectinib and M4 is over 99%. The enzyme mainly responsible for alectinib metabolism is CYP3A4; other CYP enzymes and aldehyde dehydrogenases only play a small role. Alectinib and M4 account for 76% of the circulating substance, while the rest are minor metabolites.

    Plasma half-life of alectinib is 32.5 hours, and that of M4 is 30.7 hours. 98% are excreted via the faeces, of which 84% are unchanged alectinib and 6% are M4. Less than 1% are found in the urine.

    Chemistry

    Alectinib has a pKa of 7.05. It is used in form of the hydrochloride, which is a white to yellow-white lumpy powder.

    External links

    • "Alectinib". Drug Information Portal. U.S. National Library of Medicine.

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