Osimertinib

Osimertinib
Names
Trade namesTagrisso, others
Other namesAZD9291, mereletinib, osimertinib mesilate (JAN JP), osimertinib mesylate (USAN US)
IUPAC name
  • N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-4-methoxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide
Clinical data
Drug classTyrosine kinase inhibitor[1]
Main usesNon-small-cell lung cancer (NSCLC)[2]
Side effectsDiarrhea, rash, sore mouth, tiredness, liver inflammation[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: D
    Routes of
    use    		By mouth tablets
    Typical dose80 mg OD[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa616005
    Legal
    License data
    Legal status
    Pharmacokinetics
    Protein bindingProbably high[3]
    MetabolismOxidation (CYP3A)
    Elimination half-life48 hours
    ExcretionFeces (68%), urine (14%)
    Chemical and physical data
    FormulaC28H33N7O2
    Molar mass499.619 g·mol−1
    3D model (JSmol)
    SMILES
    • CN1C=C(C2=CC=CC=C21)C3=NC(=NC=C3)NC4=C(C=C(C(=C4)NC(=O)C=C)N(C)CCN(C)C)OC
    InChI
    • InChI=1S/C28H33N7O2/c1-7-27(36)30-22-16-23(26(37-6)17-25(22)34(4)15-14-33(2)3)32-28-29-13-12-21(31-28)20-18-35(5)24-11-9-8-10-19(20)24/h7-13,16-18H,1,14-15H2,2-6H3,(H,30,36)(H,29,31,32)
    • Key:DUYJMQONPNNFPI-UHFFFAOYSA-N

    Osimertinib, sold under the brand name Tagrisso, is a medication used to treat non-small-cell lung cancer (NSCLC) with certain mutations in the EGFR gene.[2] It is taken by mouth.[1]

    Common side effects include diarrhea, rash, sore mouth, tiredness, and liver inflammation.[1] Other side effects may include pneumonitis, QT prolongation, cardiomyopathy, and eye inflammation.[1] Use in pregnancy may harm the baby.[1] It is a tyrosine kinase inhibitor.[1]

    Osimertinib was approved for medical use in the United States in 2015 and in Europe in 2016.[1][2] In the United Kingdom it costs the NHS about £5,800 per month as of 2021.[4] In the United States this amount costs about 16,000 USD.[5]

    Medical uses

    Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), if the cancer cells are positive for the T790M mutation in the gene coding for EGFR or for activating EGFR mutations.[3] The T790M mutation may be de novo or acquired following first-line treatment with other tyrosine kinase inhibitors (TKIs), such as gefitinib and afatinib.[6]

    In the US, EGFR exon 19 deletions, exon 21 L858R mutations or the T790M status of the patient prior to treatment with osimertinib must be detected by a federally approved companion diagnostic test.[3] The Food and Drug Administration (FDA) has approved FoundationOne CDx as one available companion diagnostic test for this purpose.[7] In Europe and elsewhere, activating EGFR mutations or T790M mutations may be determined by a validated test.[8]

    In people treated with osimertinib, resistance usually develops within approximately 10 months.[9] Resistance mediated by an exon 20 C797S mutation accounts for the majority of resistance cases.[10]

    It can cause fetal harm, so should not be used in women who are pregnant, and women who take it should avoid becoming pregnant.[3][11]

    Caution should be taken in people with a history of interstitial lung disease (ILD), as they were excluded from clinical trials, since the drug can cause severe ILD or pneumonitis. Caution should also be taken in people with a predisposition to long QT syndrome as the drug can provoke this.[3]

    Dosage

    It is taken at a dose of 80 mg once per day.[2]

    Side effects

    Very common (greater than 10% ) side effects include diarrhea, stomatitis, rashes, dry or itchy skin, infections where finger or toenails abut skin, low platelet counts, low leukocyte counts, and low neutrophil counts.[12]

    Common (between 1% and 10% of clinical trial subjects) adverse effects include interstitial lung disease.[12]

    Interactions

    Osimertinib is metabolized by CYP3A4 and CYP3A5, so substances that strongly inhibit either enzyme, like macrolide antibiotics, antifungals, and antivirals may increase exposure to osimertinib, and substances like rifampicin that activate either enzyme may decrease the effectiveness of osimertinib.[3][12]

    Pharmacology

    Osimertinib binds irreversibly to epidermal growth factor receptor proteins expressed by EGFR with a T790M mutation;[12] it also binds irreversibly to EGFR with an L858R mutation and with an exon 19 deletion.[3]

    It exhibits linear pharmacokinetics; the median time to Cmax is 6 hours (range 3–24 hours). The estimated mean half-life is 48 hours, and oral clearance (CL/F) is 14.3 (L/h).[3] 68% of elimination is by feces and 14% by urine.[3]

    Chemistry

    Osimertinib is provided as the mesylate; the chemical formula is C28H33N7O2·CH4O3S, and the molecular weight is 596 g/mol. The chemical name is N-(2-{2-dimethylaminoethyl-methylamino}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide mesylate salt.[3]

    History

    The drug discovery program that led to osimertinib started in 2009 and yielded the drug by 2012; the process was structure-driven and aimed to find a third generation EGFR inhibitor that would selectively target the T790M form of the EGFR receptor.[13]

    Osimertinib was designated as a Breakthrough Therapy in April 2014, based on Phase I trial results,[13] and the drug was provisionally approved under the FDA accelerated approval program with a priority review voucher, in November 2015.[14][15]

    In February 2016, the EMA provisionally approved osimertinib under an accelerated process—the first approval under the program.[13][2]

    Society and culture

    Economics

    At launch, AstraZeneca priced the drug at $12,750 per month.[16]: 59 

    Research

    As of  2020, several clinical trials are ongoing.[17]

    References

    1. 1 2 3 4 5 6 7 8 "Osimertinib Monograph for Professionals". Drugs.com. Archived from the original on 21 January 2021. Retrieved 9 November 2021.
    2. 1 2 3 4 5 6 7 "Tagrisso EPAR". European Medicines Agency (EMA). Archived from the original on 17 October 2020. Retrieved 16 October 2020.
    3. 1 2 3 4 5 6 7 8 9 10 11 "Tagrisso- osimertinib tablet, film coated". DailyMed. 5 June 2020. Archived from the original on 29 October 2020. Retrieved 16 October 2020.
    4. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 1038. ISBN 978-0857114105.
    5. ↑ "Tagrisso Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 5 May 2021. Retrieved 9 November 2021.
    6. ↑ Xu M, Xie Y, Ni S, Liu H (May 2015). "The latest therapeutic strategies after resistance to first generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in patients with non-small cell lung cancer (NSCLC)". Annals of Translational Medicine. 3 (7): 96. doi:10.3978/j.issn.2305-5839.2015.03.60. PMC 4430733. PMID 26015938.
    7. ↑ Health, Center for Devices and Radiological. "In Vitro Diagnostics - List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools)". www.fda.gov. Archived from the original on 2018-01-25. Retrieved 2018-01-17.
    8. ↑ "European Tagrisso information" (PDF). European Medicines Agency. Archived (PDF) from the original on 2018-01-17. Retrieved 2018-01-17.
    9. ↑ Patel H, Pawara R, Ansari A, Surana S (December 2017). "Recent updates on third generation EGFR inhibitors and emergence of fourth generation EGFR inhibitors to combat C797S resistance". European Journal of Medicinal Chemistry. 142: 32–47. doi:10.1016/j.ejmech.2017.05.027. PMID 28526474.
    10. ↑ Wang S, Song Y, Liu D (January 2017). "EAI045: The fourth-generation EGFR inhibitor overcoming T790M and C797S resistance". Cancer Letters. 385: 51–54. doi:10.1016/j.canlet.2016.11.008. PMID 27840244.
    11. ↑ Bollinger, Meredith K; Agnew, Amanda S; Mascara, Gerard P (July 2018). "Osimertinib: A third-generation tyrosine kinase inhibitor for treatment of epidermal growth factor receptor-mutated non-small cell lung cancer with the acquired Thr790Met mutation". Journal of Oncology Pharmacy Practice. 24 (5): 379–388. doi:10.1177/1078155217712401. ISSN 1078-1552. PMID 28565936. S2CID 206671000.
    12. 1 2 3 4 "UK label". UK Electronic Medicines Compendium. 26 January 2017. Archived from the original on 27 February 2017. Retrieved 27 February 2017.
    13. 1 2 3 Yver A (June 2016). "Osimertinib (AZD9291)-a science-driven, collaborative approach to rapid drug design and development". Annals of Oncology. 27 (6): 1165–70. doi:10.1093/annonc/mdw129. PMID 26961148.
    14. ↑ "Approved Drugs - Osimertinib". U.S. Food and Drug Administration (FDA). November 13, 2015. Archived from the original on February 27, 2017. Retrieved February 27, 2017.
    15. ↑ "Tagrisso (osimertinib) tablets". U.S. Food and Drug Administration (FDA). 22 December 2015. Archived from the original on 17 October 2020. Retrieved 16 October 2020.
    16. ↑ "AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report Priority Area 02: Cancer" (PDF). AHRQ. December 2015. Archived from the original (PDF) on 2017-04-30. Retrieved 2017-02-27.
    17. ↑ "Search of: Osimertinib - List Results - ClinicalTrials.gov". clinicaltrials.gov. Archived from the original on 2021-10-26. Retrieved 2020-04-27.
    • "Osimertinib". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2021-07-25. Retrieved 2021-07-23.
    • "Osimertinib mesylate". Drug Information Portal. U.S. National Library of Medicine. Archived from the original on 2020-10-18. Retrieved 2021-07-23.
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