Trade names Tagrisso, Tagrix Routes of
administration Oral tablets Legal status US: ℞-only | AHFS/Drugs.com tagrisso ATC code L01XE35 (WHO) Protein binding Probably high | |
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Osimertinib (previously known as mereletinib or AZD9291; trade name Tagrisso) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) drug developed by AstraZeneca Pharmaceuticals – for mutated EGFR cancers.
Contents
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. 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.
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.
It causes fetal harm, so should not be used in women who are pregnant, and women who take it should avoid becoming pregnant.
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.
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.
Common (between 1% and 10% of clinical trial subjects) adverse effects include interstitial lung disease.
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.
Pharmacology
Osimertinib binds irreversibly to epidermal growth factor receptor proteins expressed by EGFR with a T790M mutation; it also binds irreversibly to EGFR with a L858R mutation and with an exon 19 deletion.
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.
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.
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.
Osimertinib was designated as a Breakthrough Therapy in April 2014 based on Phase I trial results, and the drug was provisionally approved under the FDA accelerated approval program with a priority review voucher, in November 2015.
In February 2016 the EMA provisionally approved osimertinib under an accelerated process—the first approval under the program.
Society and culture
At launch, Astrazeneca priced the drug at $12,750 per month.
Research
As of December 2016 several clinical trials were ongoing.