Alectinib

Alectinib
Names
Pronunciation/əˈlɛktɪnɪb/ ə-LEK-ti-nib
Trade namesAlecensa
IUPAC name
  • 9-Ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesNon-small-cell lung cancer (NSCLC)[2]
Side effectsTiredness, constipation, swelling, muscle pain, low red blood cells[3]
Pregnancy
category
  • AU: D
  • US: N (Not classified yet)
    Routes of
    use    		By mouth (capsules)
    Typical dose600 mg BID[1]
    External links
    AHFS/Drugs.comMonograph
    US NLMAlectinib
    MedlinePlusa616007
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability37% (under fed conditions)
    Protein binding>99%
    MetabolismMainly CYP3A4
    MetabolitesM4 (active)
    Elimination half-life33 hours (alectinib), 31 hours (M4)
    ExcretionFeces (98%)[4]
    Chemical and physical data
    FormulaC30H34N4O2
    Molar mass482.628 g·mol−1
    3D model (JSmol)
    SMILES
    • CCc1cc2c(cc1N3CCC(CC3)N4CCOCC4)C(c5c(c6ccc(cc6[nH]5)C#N)C2=O)(C)C
    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 COPY
    • Key:KDGFLJKFZUIJMX-UHFFFAOYSA-N

    Alectinib, sold under the brand name Alecensa, is a medication used to treat non-small-cell lung cancer (NSCLC).[2] It is used for advanced disease that is anaplastic lymphoma kinase (ALK) positive.[2] It is taken by mouth.[1]

    Common side effects include tiredness, constipation, swelling, muscle pain, and low red blood cells.[3] Other side effects may include liver problems, pneumonitis, kidney problems, and muscle breakdown.[3] Use in pregnancy may harm the baby.[3] It is a tyrosine kinase inhibitor that blocks ALK.[1][2]

    Alectinib was approved in Japan in 2014, the United States in 2015, and Europe in 2017.[3][2][5] In the United Kingdom 4 weeks costs the NHS about £5,000 as of 2021.[1] This amount in the United States is about 16,000 USD.[6]

    Medical uses

    It is used to treat ALK fusion-gene positive, unresectable, advanced or recurrent non-small-cell lung cancer (NSCLC).[7]

    In November 2017 the FDA approved alectinib for the first-line treatment of patients with ALK-positive metastatic non-small cell lung cancer.[8] This based on the phase 3 ALEX trial comparing it with crizotinib.[8]

    Dosage

    It is typically used at a dose of 600 mg twice per day.[1]

    Contraindications

    There are no contraindications under the US approval.[9] The European approval only has the default remark about hypersensitivity being a contraindication.[10]

    Side effects

    Alectinib-induced erythema multiforme

    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%).[11] Serious side effects occurred in 19% of patients; fatal ones in 2.8%.[9]

    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.[11][10]

    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.[11][10]

    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.[12]

    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.[11][12]

    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.[11][12]

    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.[9]

    History

    It was granted an accelerated approval by the US Food and Drug Administration (FDA) in December 2015 to treat patients with advanced ALK-positive NSCLC whose disease worsened after, or who could not tolerate, treatment with crizotinib (Xalkori).[13] This was converted into a full approval in Nov 2017.[8]

    It got a conditional approval by the European Medicines Agency in February 2017 for the same indication. This means that additional studies are awaited to confirm a positive benefit-risk-ratio.[14]

    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%.[7] 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.[15]

    References

    1. 1 2 3 4 5 6 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1012. ISBN 978-0857114105.
    2. 1 2 3 4 5 "Alecensa". Archived from the original on 13 October 2021. Retrieved 13 January 2022.
    3. 1 2 3 4 5 "DailyMed - ALECENSA- alectinib hydrochloride capsule". dailymed.nlm.nih.gov. Archived from the original on 9 November 2021. Retrieved 13 January 2022.
    4. ↑ "Alecensa (alectinib) Capsules, for Oral Use. Full Prescribing Information" (PDF). Genentech USA, Inc. Archived (PDF) from the original on 11 February 2017. Retrieved 8 February 2017.
    5. ↑ Takiguchi, Yuichi (24 January 2017). Molecular Targeted Therapy of Lung Cancer. Springer. p. 128. ISBN 978-981-10-2002-5. Archived from the original on 14 January 2022. Retrieved 13 January 2022.
    6. ↑ "Alecensa Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 14 April 2021. Retrieved 13 January 2022.
    7. 1 2 McKeage K (January 2015). "Alectinib: a review of its use in advanced ALK-rearranged non-small cell lung cancer". Drugs. 75 (1): 75–82. doi:10.1007/s40265-014-0329-y. PMID 25428710. S2CID 34062880.
    8. 1 2 3 "FDA approves Alecensa for ALK-positive metastatic non-small cell lung cancer Nov 2017". Archived from the original on 9 December 2017. Retrieved 30 June 2021.
    9. 1 2 3 FDA Professional Drug Information on Alecensa.
    10. 1 2 3 "Alecensa: EPAR – Product Information" (PDF). European Medicines Agency. 16 May 2017. Archived (PDF) from the original on 17 April 2018. Retrieved 30 June 2021.
    11. 1 2 3 4 5 Haberfeld, H, ed. (2017). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Alecensa 150 mg Hartkapseln.{{cite book}}: CS1 maint: unrecognized language (link)
    12. 1 2 3 "Alecensa: Assessment report" (PDF). European Medicines Agency. 15 December 2016. Archived (PDF) from the original on 20 September 2018. Retrieved 30 June 2021.
    13. ↑ "New Oral Therapy To Treat ALK-Positive Lung Cancer. Dec 2015". Archived from the original on 16 February 2016. Retrieved 30 June 2021.
    14. ↑ "Alecensa authorisation details". European Medicines Agency. 16 February 2017. Archived from the original on 20 June 2018. Retrieved 15 March 2022.
    15. ↑ "Chugai's ALK Inhibitor "Alecensa" Trial Stopped Early for Benefit. Feb 2016" (PDF). Archived from the original (PDF) on 18 April 2016. Retrieved 30 June 2021.
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