Ceritinib

Ceritinib
Names
PronunciationCeritinib: /səˈrɪtɪnɪb/ sə-RIT-i-nib
Zykadia: /zaɪˈkeɪdiːə/ zy-KAY-dee-ə
Trade namesZykadia, Spexib, others
Other namesLDK378
IUPAC name
  • 5-Chloro-N2-{5-methyl-4-(piperidin-4-yl)-2-[(propan-2-yl)oxy]phenyl}-N4-[2-(propane-2-sulfonyl)phenyl]pyrimidine-2,4-diamine
Clinical data
Drug classALK inhibitor[1]
Main usesNon-small cell lung cancer (NSCLC)[1]
Side effectsDiarrhea, nausea, tiredness, liver problems, weight loss, rash, kidney problems, low red blood cells[1]
Pregnancy
category
  • US: D (Evidence of risk)
    Routes of
    use    		By mouth (capsules)
    Typical dose450 mg OD[1]
    External links
    AHFS/Drugs.comMonograph
    US NLMCeritinib
    Legal
    License data
    Legal status
    Pharmacokinetics
    BioavailabilityNot determined
    Protein binding97%
    MetabolismCYP3A
    Elimination half-life41 hours
    ExcretionFeces (92.3%), urine (1.3%)[2]
    Chemical and physical data
    FormulaC28H36ClN5O3S
    Molar mass558.14 g·mol−1
    3D model (JSmol)
    SMILES
    • CC1=CC(=C(C=C1C2CCNCC2)OC(C)C)NC3=NC=C(C(=N3)NC4=CC=CC=C4S(=O)(=O)C(C)C)Cl
    InChI
    • InChI=1S/C28H36ClN5O3S/c1-17(2)37-25-15-21(20-10-12-30-13-11-20)19(5)14-24(25)33-28-31-16-22(29)27(34-28)32-23-8-6-7-9-26(23)38(35,36)18(3)4/h6-9,14-18,20,30H,10-13H2,1-5H3,(H2,31,32,33,34)
    • Key:VERWOWGGCGHDQE-UHFFFAOYSA-N

    Ceritinib, sold under the brand name Zykadia among others, is a medication used to treat non-small cell lung cancer (NSCLC).[1] Specifically it is used for advanced disease that is anaplastic lymphoma kinase (ALK) positive.[1] It is taken by mouth.[3]

    Common side effects include diarrhea, nausea, tiredness, liver problems, weight loss, rash, kidney problems, and low red blood cells.[1] Other side effects may include high blood sugar, pneumonitis, QT prolongation, and pancreatitis.[1][3] Use in pregnancy may harm the baby.[3] It is a tyrosine kinase inhibitor, specifically a ALK inhibitor.[1][4]

    Ceritinib was approved for medical use in the United States in 2014 and Europe in 2015.[1] In the United Kingdom 4 weeks of treatment costs the NHS about £2,800 as of 2021.[4] This amount in the United States is about 10,400 USD.[5]

    Medical uses

    Ceritinib is an anaplastic lymphoma kinase (ALK) inhibitor primarily used for the treatment of ALK positive metastatic NSCLC.[6][7] Previously, it was only indicated for patients who had developed resistant to crizotinib, another ALK inhibitor, but has since had its usage expanded to serve as a primary option for metastatic NSCLC.[8]

    Dosage

    The typical dose is 450 mg once per day.[1]

    Side effects

    Serious side effects include gastrointestinal toxicity, hepatotoxicity, interstitial lung disease, prolonged QT syndrome, hyperglycemia, bradycardia, and pancreatitis.[9][10]

    The most commonly reported side effects were diarrhea, nausea, elevated liver enzymes, vomiting, abdominal pain, fatigue, decreased appetite, and constipation.[6] Due to the risk of elevated liver enzymes, it is recommended that liver function tests be performed every two weeks for the first 9 weeks of treatment.[11]

    Interactions

    Ceritinib is both a substrate and potent inhibitor of the enzyme CYP3A4, so medications that have affinity for this enzyme may interact with ceritinib.[10]

    Pharmacology

    Mechanism of action

    Ceritinib is a tyrosine kinase inhibitor that selectively and potently inhibits anaplastic lymphoma kinase (ALK). In normal physiology, ALK functions as a key step in the development and function of nervous system tissue. However, chromosomal translocation and fusion give rise to an oncogenic form of ALK that has been implicated in progression of NSCLC. Ceritinib thus acts to inhibit this mutated enzyme and stop cell proliferation, ultimately halting cancer progression.[12] Because ceritinib is considered a targeted cancer therapy, an FDA-approved test is required to determine which patients are candidates for ceritinib. This test, developed by Roche, is the VENTANA ALK (D5F3) CDx Assay and is used to identify ALK-positive NSCLC patients who would benefit from ceritinib treatment.[13]

    Society and culture

    Names

    Ceritinib is the INN.[14]

    Commercialization

    Zykadia is manufactured by Novartis.[15] Created in 1996 from a merger between Ciba-Geigy and Sandoz, Novartis is a global corporation based out of Basel, Switzerland.[16] Over 155 countries worldwide have Novartis products available for use.[17] Financial data from 2016 reveals net sales of $48.5 billion for the Swiss company.[17]

    Novartis divides its shares into two major market exchanges: the ordinary shares (NOVN SW) trade in the Six Swiss Exchange while the American Depositary Receipts (NVS US) trade in the New York Stock Exchange.[18] Nominees, fiduciaries, and ADR depositary make up the bulk of registered shareholders of Novartis stock while individual shareholders make up the lowest percentage.[19]

    Originally launched in 2014, Zykadia sales for Fiscal Year 2016 reached $91 million.[20] While this is substantially less than several of their other pharmaceuticals, the new indication introduced in 2017 should result in increased sales of the drug. GlobalData predicts ceritinib sales to exceed $127million by 2025, while sustaining a compounded annual growth rate of 10.7%.[21]

    Intellectual property

    Novartis currently owns twelve patents on Zykadia.[22] The patents relate to different structures of the chemical compound as well as methodologies for manufacturing the drug. For example, one patent examines the structure of pyrimidines and their use in treatment of neoplastic diseases.[23] Others examine the composition of protein kinase inhibitors.[24] The most recent patents are specific the methodologies of using ALK inhibitors.[25]

    Research

    Researchers first identified the ALK fusion gene in 1994. Several years later, Novartis Pharmaceuticals Corporation, began working towards development of targeted ALK inhibitors. In April 2014, the FDA granted accelerated approval for ceritinib when used for ALK-positive NSCLC patients who have progressed on or are intolerant to crizotinib (Xalkori, Pfizer, Inc.). This rapid approval was determined from a multi-center clinical trial in which 163 patients who had disease progression or were intolerant to crizotinib received oral ceritinib 750 mg once daily. This trial demonstrated an objective response rate (ORR) of 44% and a median duration of response (DOR) of 7.1 months, both of which were favorable compared to the worsening or failed use of crizotinib.[26]

    In February 2017, the FDA accepted a supplement New Drug Application for ceritinib and granted Priority Review for expanded use of ceritinib. Specifically, it became a first-line therapy option for metastatic NSCLC with ALK-positive tumors. Additionally, the FDA also gave Breakthrough Therapy designation to the drug for ALK-positive metastatic NSCLC that has metastasized to the brain.[27] This new designation resulted from the ASCEND-4 clinical trial, which was a randomized, phase III study that compared the use of ceritinib to standard-of-care platinum-based chemotherapy treatments. Median progression-free survival was 16.6 months for ceritinib (n=189) versus 8.1 months in the chemotherapy-treated patients (n=187).[28]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 "Zykadia". Archived from the original on 13 October 2021. Retrieved 3 January 2022.
    2. ↑ "Zykadia (ceritinib) Capsules, for Oral Use. Full Prescribing Information" (PDF). Novartis Pharmaceuticals Corporation. Archived (PDF) from the original on 28 April 2019. Retrieved 14 February 2017.
    3. 1 2 3 "DailyMed - ZYKADIA- ceritinib tablet, film coated". dailymed.nlm.nih.gov. Archived from the original on 24 March 2021. Retrieved 3 January 2022.
    4. 1 2 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1018. ISBN 978-0857114105.
    5. ↑ "Ceritinib Prices, Coupons & Savings Tips - GoodRx". GoodRx. Retrieved 3 January 2022.
    6. 1 2 "Prescribing data" (PDF). www.pharma.us.novartis.com. Archived (PDF) from the original on 2019-04-28. Retrieved 2019-06-12.
    7. ↑ Deeks, Emma D. (2016). "Ceritinib: a Review in ALK-Positive Advanced NSCLC". Targeted Oncology. 11 (5): 693–700. doi:10.1007/s11523-016-0460-7. ISSN 1776-260X. PMID 27699584.
    8. ↑ "FDA Expands Ceritinib Approval for Lung Cancer". National Cancer Institute. 27 June 2017. Archived from the original on 11 July 2021. Retrieved 25 August 2021.
    9. ↑ Au, Trang H.; Cavalieri, Courtney C.; Stenehjem, David D. (2017). "Ceritinib: A primer for pharmacists". Journal of Oncology Pharmacy Practice. 23 (8): 602–614. doi:10.1177/1078155216672315. PMID 27738095. S2CID 12034087. Archived from the original on 2021-01-21. Retrieved 2021-08-25.
    10. 1 2 "Login". online.lexi.com. Archived from the original on 2019-03-06. Retrieved 2021-08-25.
    11. ↑ "Anapestic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer". UpToDate. Wolters Kluwer. Archived from the original on 2 November 2017. Retrieved 30 October 2017.
    12. ↑ "Analplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer". UpToDate. Wolters Kluwer. Archived from the original on 2 November 2017. Retrieved 30 October 2017.
    13. ↑ "Roche announces FDA approval of companion diagnostic to identify ALK-positive non-small cell lung cancer patients". diagnostics.roche.com. Archived from the original on 2019-04-26. Retrieved 2021-08-25.
    14. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 71" (PDF). World Health Organization. 2014. p. 79. Archived (PDF) from the original on 17 May 2016. Retrieved 14 February 2017.
    15. ↑ "Brochure" (PDF). www.us.zykadia.com. Archived from the original (PDF) on 2017-11-07. Retrieved 2019-06-12.
    16. ↑ "Novartis Company History". Novartis Global. Archived from the original on 7 November 2017. Retrieved 3 November 2017.
    17. 1 2 "Novartis Annual Reporting Suite". Novartis. Archived from the original on 2021-10-09. Retrieved 2021-08-25.
    18. ↑ "Share Overview". Novartis. Archived from the original on 2021-10-09. Retrieved 2021-08-25.
    19. ↑ "Share Ownership". Novartis. Archived from the original on 2021-01-27. Retrieved 2021-08-25.
    20. ↑ "Interim financial report" (PDF). www.novartis.com. 2017. Archived from the original (PDF) on 2020-12-04. Retrieved 2019-06-12.
    21. ↑ Xuan C, Gunduz V. "NSCLC MARKET – Global Drug Forecast & Market Analysis to 2025". Drug Development & Delivery. No. November–December 2016. Archived from the original on 2019-08-27. Retrieved 2021-08-25.
    22. ↑ "Zykadia - Patents - Expiry - Expiration - Dates". PharmaCompass.com. Archived from the original on 2019-04-26. Retrieved 2021-08-25.
    23. ↑ "US Patent No.: 7964592" (PDF). PharmaCompass. Archived (PDF) from the original on 27 August 2021. Retrieved 1 November 2017.
    24. ↑ "US No.: 8399450". PharmaCompass. Archived from the original on 7 November 2017. Retrieved 1 November 2017.
    25. ↑ "US No.: 8703787". PharmaCompass. Archived from the original on 7 November 2017. Retrieved 1 November 2017.
    26. ↑ Khozin S, Blumenthal GM, Zhang L, Tang S, Brower M, Fox E, et al. (June 2015). "FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer". Clinical Cancer Research. 21 (11): 2436–9. doi:10.1158/1078-0432.CCR-14-3157. PMID 25754348. Archived from the original on 2021-01-28. Retrieved 2021-08-25.
    27. ↑ "Novartis drug Zykadia receives FDA Priority Review for first-line use in patients with ALK+ metastatic NSCLC". Novartis. Archived from the original on 2019-04-26. Retrieved 2021-08-25.
    28. ↑ Soria JC, Tan DS, Chiari R, Wu YL, Paz-Ares L, Wolf J, et al. (March 2017). "First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study". Lancet. 389 (10072): 917–929. doi:10.1016/s0140-6736(17)30123-x. PMID 28126333. S2CID 4739527.
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