Osimertinib

Breast Feeding; Lactation; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors; Signal Transduction Inhibitors

EMA approved medicines: Human medicine

Danger

H302 (50%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P264, P270, P272, P273, P280, P301+P317, P302+P352, P318, P319, P321, P330, P333+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 2 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Elevations in serum aminotransferase levels are uncommon during osimertinib therapy occurring in 4% to 5% of patients and rising above 5 times the upper limit of the normal range in only 1% or less. In preregistration trials, there was a single incidence of clinically apparent liver injury attributed to osimertinib therapy, but the clinical features and relatedness to therapy were not defined. Since its approval and more widespread use, there have been no published cases of liver injury due to osimertinib.

L - Antineoplastic and immunomodulating agents

QL - Antineoplastic and immunomodulating agents

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain mutant forms of EGFR (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumours following treatment with first-line EGFR-TKIs. As a third-generation tyrosine kinase inhibitor, osimertinib is specific for the gate-keeper T790M mutation which increases ATP binding activity to EGFR and results in poor prognosis for late-stage disease. Furthermore, osimertinib has been shown to spare wild-type EGFR during therapy, thereby reducing non-specific binding and limiting toxicity. Compared to wild-type EGFR, osimertinib has 200 times higher affinity for EGFR molecules with the L858R/T790M mutation _in vitro_.

Osimertinib is metabolized to at least two pharmacologically active metabolites, AZ7550 and AZ5104, that circulate at approximately 10% of the concentration of the parent compound. Biochemical assays have shown that AZ7550 has similar potency and efficacy to osimertinib, while AZ5104 is more potent against mutant and wild-type EGFR. The main metabolic pathways are oxidation (predominantly by CYP3A) and dealkylation.

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OSIMERTINIB

Established Pharmacologic Class [EPC] - Kinase Inhibitor

Mechanisms of Action [MoA] - Kinase Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A Inhibitors

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inducers

Substances that inhibit or prevent the proliferation of NEOPLASMS.

Protein kinase inhibitors that inhibit TYROSINE PROTEIN KINASES.

The median time to Cmax was found to be 6 hours.

Osimertinib is primarily eliminated through excretion in the feces (68%), to a lesser extent through urine (14%), while only 2% is excreted unchanged.

The mean volume of distribution at steady state is 918 L.

Oral clearance is 14.3 L/hr.