Osimertinib

Osimertinib
Clinical data
Trade names Tagrisso, Tagrix
AHFS/Drugs.com tagrisso
Routes of
administration		 Oral tablets
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding Probably high[1]
Metabolism Oxidation (CYP3A)
Biological half-life 48 hours
Excretion Feces (68%), urine (14%)
Identifiers
Synonyms AZD9291
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C28H33N7O2
Molar mass 499.62 g·mol−1
3D model (JSmol)

Osimertinib (previously known as mereletinib or AZD9291; trade name Tagrisso)[2][3] is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug[4][5] developed by AstraZeneca Pharmaceuticals – for mutated EGFR cancers.

Medical uses

Osimertinib is used to treat locally advanced or metastatic non-small-cell lung cancer (NSCLC), when the cancer has the specific T790M mutation in the gene coding for epidermal growth factor receptor.[1][6] In the US the mutation must be detected with an FDA-approved companion diagnostic test, and the person must have been stopped responding to the other EGFR-inhibitors.[1][7]

The NSCLC in people receiving the drug has developed resistance mutations, namely C797S occurs in EGFR exon 20 or amplifications of the EGFR gene, even as T790M clones have been eliminated.[8]

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.[9]

Osimertinib was designated as a Breakthrough Therapy in April 2014 based on Phase I trial results,[9] and the drug was provisionally approved under the FDA accelerated approval program with a priority review voucher, in November 2015.[10]

In February 2016 the EMA provisionally approved osimertinib under an accelerated process—the first approval under the program.[9]

Society and culture

At launch, Astrazeneca priced the drug at $12,750 per month.[11]:59

Research

As of December 2016 several clinical trials were ongoing.[8]

References

  1. 1 2 3 4 5 6 7 8 9 "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. PMID 26169963. doi:10.1158/1078-0432.CCR-15-1211.
  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. PMID 26370354. doi:10.1016/S1470-2045(15)00246-6.
  6. 1 2 3 4 5 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. PMC 4430733 Freely accessible. PMID 26015938. doi:10.3978/j.issn.2305-5839.2015.03.60.
  8. 1 2 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. PMC 5233880 Freely accessible. PMID 28149764.
  9. 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. PMID 26961148.
  10. ↑ "Approved Drugs - Osimertinib". FDA Center for Drug Evaluation and Research. November 13, 2015.
  11. ↑ "AHRQ Healthcare Horizon Scanning System – Potential High-Impact Interventions Report Priority Area 02: Cancer" (PDF). AHRQ. December 2015.
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