Osimertinib 80mg Astrazeneca treats lung cancer without small cells (1 blister x 10 tablets)

osimertinib is a Tyrosine Kinase inhibitor (TKI). This is an unfavorable inhibitor of epidermal growth factor receptors (EGFRS) with sensitive mutations (EGFRM) and Mutations T790M resistance to TKI.

Pharmaceutical impact

In vitro studies have shown that Osimertinib has a highly effective inhibiting EGFR receptor with steps of treatment of non-small cell cancer cells with T790M mutations and clinically sensitive eGFRM (Phosphorus-EGFR test shows ICSOS clearly from 6 Nm to 54Nm). This leads to inhibition of cell growth while showing that there is little significant impact on the EGFR of non-mutant cells (Wild-Type Cell Lines) (Phosphorus-EGFR test shows that ICSOS is clearly from 480 Nm to 1.8 Um).

When using Osimertinib orally in vivo, the tumor shrinks in both foreign and genetically modified tumors on the lungs with small -cell lung cancer cells with EGFRM and T790M mutations.

Dynamic pharmacokinetics

Osimertinib pharmacokinetics parameters are established on healthy people and patients with small cell lung cancer (NSCLC). Based on the analysis of pharmacokinetics in the research population, Osimertinib's apparent plasma clearance is 14.2 l/h, the apparent distribution integral is 997 L and the last phase selling time is about 48 hours. AUC and CMAX increases the proportion at the dose at the dose levels from 20 to 240mg.

When using Osimertinib once a day increases, accumulates about 3 times with the constant contact level achieved after 15 days of medication. In a status, the concentration of drugs in circulatory plasma maintains a typical level of 1.6 times in about 24 hours of medication.

absorption

After using oral tagrisso, the peak concentration of osimertinib in plasma is achieved at the period of median TMAX (Min-Max) is 6 hours (3-24 hours), with a few vertices recorded in the first 24 hours in some patients.

The absolute bioavailability of the tagrisso has not been determined. Based on a clinical pharmacokininese study on patients at the dose of 80 mg, food does not change the bioavailability of osimertinib to a clinical significance level. (AUC increased by 6% (90% CI -5, 19) and CMAX decreased by 7% (90% CI -19, 6)). In healthy volunteers using 1 tablet of 80 mg, the stomach pH has been raised due to the use of omeprazole for 5 days, the concentration and contact time of osimertinib has not been affected (AUC and CMAX increased, respectively 7% and 2%) with 90% CI in terms of exposure ratio within 80-125%.

distribution

The median distribution volume is estimated on the research population of Osimertinib in the Hang Dinh (VSS/F) state of 997 L showing the drug widely distributed into the tissues. Protein cohesion is not measured in plasma because of unstable, but according to the physical and chemical properties of osimertinib, the cohesion with plasma proteins is probably very high. Osimertinib has also been proved to be equivalent to plasma proteins in mice and in humans, albumin of human serum and rats and liver cells.

Biological Change

In vitro research shows that Osimertinib is metabolized mainly by CYP3A4 and CYP3A5. The metabolic process through CYP3A4 may be auxiliary transformation. The alternative transformation can exist but have not been fully described.

Based on studies in Vitro test tubes, 2 pharmacological metabolites (AZ7550 and AZ5104) were later determined in plasma in preclinical research and in people after a dose of oral with osimertinib; AZ7550 shows similar medicinal force to Tagrisso while AZ5104 shows stronger efficiency on EGFR in both mutant and non -mutant (Type Wide). Both metabolites appear slowly within plasma after the patient Tagrisso, with average TMAX (Min-Max) for metabolites AZ7550 and AZ5104 are 24 hours (4-72 hours) and 24 hours (6-72 hours).

In human plasma, Osimertinib accounts for 0.8%, with 2 distributed metabolites is 0.08% and 0.07% of the total number of radiation with most cohesive radioactive substances equivalent to plasma proteins. The average geometric exposure of both AZ5104 and AZ7550, based on AUC, is approximately 10% of osimertinib's contact when in a stable state.

The main metabolic line of osimertinib is oxidation and reducing alkylation. At least 12 components have been observed in the urine and manure samples with 5 components accounting for> 1% of the dose in which Osimertinib formsless, AZ5104 and AZ7550, accounting for about 1.9; 6.6 and 2.7% of the dose while the closed cysteinyl product (M21) and an unknown metabolite (M25) account for 1.5% and 1.9% of the dose.

Based on In vitro studies, Osimertinib is a competitive inhibitor of CYP 3A4/5 but does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6 and 2E1 at clinical concentrations. Based on In vitro studies, osimertinib is not a UGT1A1 and UGT2B7 inhibitor at the liver -related Lam Sang concentration. UGT1A1 can cause inhibition on the intestine but the clinical impact is unknown.

Elimination

After taking a single dose of 20 mg, 67.8% of the dose was detected in the feces (1.2% in constant form), while 14.2% of the dose (0.8% in constant form) was found in urine after 84 days from the date of collection of samples. Osimertinib constant accounting for about 2% of the elimination process with 0.8% in urine and 1.2% in feces.

Notify the physician the unwanted effects when using the drug.

Drug interaction

Pharmacokinetics interaction

osimertinib may increase the concentration and contact time of BCRP substrate.

Active ingredients can increase the concentration of osimertinib in plasma

In vitro studies have shown that osimertinib has been metabolized mainly through CYP3A4 and CYP3A5. In a clinical pharmacokinetic study, when used with 200 mg of otraconazole (strong CYP3A4 inhibitors) x twice a day, it did not have a significant clinical effect on the concentration and time of contact with osimertinib (area under the curve (AUC) increased 24% and CMAX decreased by 20%).

Therefore, CYP3A4 inhibitors probably do not affect the concentration and contact time of osimertinib. No further catalytic enzymes have not been identified.

Active ingredients can reduce osimertinib concentration in plasma

In a clinical pharmacokinetics study in patients, the area of ​​Osimertinib concentration under the curve at a stable stage (AUC Steady State) decreased by 78% when used with rifampicin (600 mg/day for 21 days). Similar to the concentration and time of contact with AZ5104 metabolites also decreased by 82% (for AUC values) and 78% (for CMAX values). It is recommended to avoid using Tagrisso simultaneously with strong CYP3A touch substances (E.G. Phenytoin, Rifampicin and Carbamazepine). Medium CYP3A4 touch substances (E.G. Bosentan, Efavirenz, Erravirine, Modafinil) may also reduce the concentration and time of osimertinib exposure and should be used carefully or avoid uses if possible.

There is no sieve data to recommend tagrisso dose adjustment. Contraindicated with St. John's Wort.

Effects of drugs that reduce gastric juice on osimertinib

In a clinical pharmacokinetics study, simultaneously using Omeprazole did not change the concentration and contact time of the clinical osimertinib. The gastric pH moder agents can be used with tagrisso without any restrictions.