Osimertinib

Osimertinib (previously known as mereletinib; trade name Tagrisso)[2][3] is a medication used to treat non-small-cell lung carcinomas with a specific mutation.[4][5] It is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor. Developed by AstraZeneca, the medication was approved as a cancer treatment in 2017 by both the Food and Drug Administration and the European Commission.

Osimertinib
Clinical data
Trade namesTagrisso, Tagrix
Other namesAZD9291
AHFS/Drugs.comtagrisso
License data
Routes of
administration		Oral tablets
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein bindingProbably high[1]
MetabolismOxidation (CYP3A)
Elimination half-life48 hours
ExcretionFeces (68%), urine (14%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
PDB ligand
Chemical and physical data
FormulaC28H33N7O2
Molar mass499.619 g·mol−1
3D model (JSmol)

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.[1][6] The T790M mutation may be de novo or acquired following first-line treatment with other tyrosine kinase inhibitors (TKIs), such as gefitinib and afatinib.[7]

In the USA, T790M status of the patient prior to treatment with osimertinib must be detected by a federally approved companion diagnostic test.[1] The Food and Drug Administration (FDA) has approved FoundationOne CDx for this purpose.[8] In Europe and elsewhere, T790M mutations may be determined by a validated and suitably sensitive next-generation sequencing assay.[9]

In people treated with osimertinib, resistance usually develops within approximately 10 months.[10] Resistance mediated by an exon 20 C797S mutation accounts for the majority of resistance cases.[11]

It causes fetal harm, so should not be used in women who are pregnant, and women who take it should avoid becoming pregnant.[1][6]

Caution should be taken in people with a history of interstitial lung disease (ILD) were excluded from clinical trials, as the drug can cause severe ILD or pneumonia. Caution should also be taken in people with a predisposition to long QT syndrome as the drug can provoke this.[1]

Adverse effects

Very common (greater than 10% of clinical trial subjects) adverse 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.[6]

Common (between 1% and 10% of clinical trial subjects) adverse effects include interstitial lung disease.[6]

Interactions

Osimertinib is metabolized by CYP3A4 and CYP3A5, so substances that strongly inhibit either enyzme, like macrolide antibiotics, antifungals, and antivirals may increase exposure to osimertinib, and substances like rifampicin that activate either enzyme will decrease the effectiveness of osimertinib.[1][6]

Pharmacology

Osimertinib binds irreversibly to epidermal growth factor receptor proteins expressed by EGFR with a T790M mutation;[6] it also binds irreversibly to EGFR with a L858R mutation and with an exon 19 deletion.[1]

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 14.2 (L/h). 68% of elimination is by feces and 14% by urine.[1]

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.[1]

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.[12]

Osimertinib was designated as a Breakthrough Therapy in April 2014 based on Phase I trial results,[12] and the drug was provisionally approved under the FDA accelerated approval program with a priority review voucher, in November 2015.[13]

In February 2016 the EMA provisionally approved osimertinib under an accelerated process—the first approval under the program.[12]

Society and culture

At launch, Astrazeneca priced the drug at $12,750 per month.[14]:59

Brand names

In Bangladesh it is under the trade name Tagrix.

Research

As of December 2016 several clinical trials were ongoing.[15]

References
  1. "US Label" (PDF). FDA. November 2015. Index page for NDA 208065
  2. "Osimertinib". AdisInsight. Retrieved 27 February 2017.
  3. "Proposed INN: List 113" (PDF). International Nonproprietary Names for Pharmaceutical Substances (INN). 29 (2): 285. 2015. Retrieved 16 November 2015.
  4. Ayeni D, Politi K, Goldberg SB (2015). "Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer". Clin. Cancer Res. 21 (17): 3818–20. doi:10.1158/1078-0432.CCR-15-1211. PMC 4720502. PMID 26169963.CS1 maint: uses authors parameter (link)
  5. Tan CS, Gilligan D, Pacey S (2015). "Treatment approaches for EGFR-inhibitor-resistant patients with non-small-cell lung cancer". Lancet Oncol. 16 (9): e447–59. doi:10.1016/S1470-2045(15)00246-6. PMID 26370354.CS1 maint: uses authors parameter (link)
  6. "UK label". UK Electronic Medicines Compendium. 26 January 2017. Retrieved 27 February 2017.
  7. Xu M, Xie Y, Ni S, Liu H (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)". Ann Transl Med. 3 (7): 96. doi:10.3978/j.issn.2305-5839.2015.03.60. PMC 4430733. PMID 26015938.CS1 maint: uses authors parameter (link)
  8. 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. Retrieved 2018-01-17.
  9. "European Tagrisso information" (PDF). European Medicines Agency. Retrieved 2018-01-17.
  10. Patel, Harun; Pawara, Rahul; Ansari, Azim; Surana, Sanjay (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.
  11. Wang, Shuhang; Song, Yongping; Liu, Delong (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.
  12. 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.
  13. "Approved Drugs - Osimertinib". FDA Center for Drug Evaluation and Research. November 13, 2015.
  14. "AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report Priority Area 02: Cancer" (PDF). AHRQ. December 2015.
  15. Minari, R; Bordi, P; Tiseo, M (December 2016). "Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance". Translational Lung Cancer Research. 5 (6): 695–708. doi:10.21037/tlcr.2016.12.02. PMC 5233880. PMID 28149764.
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