Osimertinib: Anticancer drug, protein kinase inhibitor

Osimertinib: Anticancer drug, protein kinase inhibitor

Blog Article

Adjuvant treatment after complete tumor resection in adult patients with stage IB-IIIA non-small cell lung cancer (NSCLC) whose tumors harbor epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutations.
Treatment of patients with locally advanced or metastatic NSCLC with activating EGFR mutations.
Treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC.
Pharmacodynamics
Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that binds to certain EGFR mutations (T790M, L858R, and exon 19 deletion) that predominate in non-small cell lung cancer (NSCLC) tumors after first-line EGFR-TKI therapy.

As a third-generation tyrosine kinase inhibitor, Osimert 80 mg (Osimertinib) is specific for the T790M gate-keeper mutation, which increases ATP binding activity to EGFR and is associated with poor prognosis in advanced disease. Furthermore, osimertinib has been shown to cleave wild-type EGFR during treatment, thereby reducing nonspecific binding and limiting toxicity.

Dynamics
Absorption
Peak plasma concentrations are achieved approximately 6 hours (range 3–24 hours) after oral administration.

Dose-proportional increases in AUC and peak plasma concentrations were observed in the dose range of 20–240 mg.

Steady-state concentrations are achieved within approximately 15 days.

The mean volume of distribution at steady state was 986 L.

Distribution
There is no information on whether osimertinib is distributed into milk. Limited animal data suggest that the drug is distributed into the brain.

Plasma protein binding is 95%.

Transformation
Osimertinib is metabolized to at least two pharmacologically active metabolites, AZ7550 and AZ5104, which 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 major metabolic pathways are oxidation (primarily by CYP3A) and dealkylation.

Elimination
Osimertinib is eliminated primarily via fecal excretion (68%), to a lesser extent via urine (14%), while only 2% is excreted unchanged. The estimated population mean elimination half-life is 48 hours.

Drug interactions
Interactions with other drugs
Strong CYP3A4 inducers may decrease osimertinib exposure. Osimertinib may increase exposure of breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) substrates.

Moderate CYP3A4 inducers (eg, bosentan , efavirenz , etravirine , modafinil ) may also decrease osimertinib exposure and should be used with caution or avoided when possible.

Drugs that increase the effect when used concurrently with osimertinib: Rosuvastatin , fexofenadine , digoxin , dabigatran, aliskiren.

Drugs that reduce the effect when used concurrently with osimertinib: Simvastatin .

Concomitant use of osimertinib with drugs transported by the breast cancer resistance protein may increase plasma concentrations of the substrate.

Avoid concomitant use with drugs that prolong the QT interval.

Rifampin decreased peak plasma concentrations and AUC of osimertinib.

Food Interactions
Avoid St. John's Wort. This herb induces the CYP3A metabolism of osimertinib, and therefore, dose adjustment is required if they must be used concomitantly.

Take with or without food.

Contraindications
Hypersensitivity to the active substance or to any of the excipients.
St. John's Wort should not be used with osimertinib.
Dosage & Administration
Adult
The recommended dose is 80 mg/time/day.

Dose interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, the dose should be reduced to 40 mg/day.

If the QTc interval is > 500 milliseconds on at least 2 separate ECGs, discontinue treatment. If the QTc interval improves to < 481 milliseconds or returns to baseline (if the baseline QTc interval was ≥ 481 milliseconds), treatment may be resumed at a reduced dose of 40 mg daily.

If coadministered with a strong CYP3A inducer, increase the osimertinib dose to 160 mg daily.

Other objects
No dosage adjustment is required due to patient age, body weight, gender, ethnicity and smoking status, hepatic impairment, renal impairment.

 

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