Osimert

Osimertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR). It binds irreversibly to certain mutant forms of EGFR (T790M, L858R and exon 19 deletion) at about 9-fold lower concentrations than wild-type EGFR. In cultured cells and animal tumor implantation models, it showed anti-tumor activity against NSCLC lines with EGFR mutations (T790M/L858R, L858R, T790M/exon 19 deletion, and exon 19 deletion). It was less active against wild-type EGFR amplifications. Two pharmacologically active metabolites, AZ7550 and AZ5104, have been identified in plasma after oral use. They circulate at about 10% of the parent drug and have similar inhibitory profiles. AZ7550 showed similar potency to osimertinib, while AZ5104 was more potent against exon 19 deletion and T790M mutants (about 8-fold) and wild-type EGFR (about 15-fold). In vitro, osimertinib also inhibited the activity of HER2, HER3, HER4, ACK1 and BLK at clinically relevant concentrations.

After oral dosing, the area under the plasma concentration-time curve (AUC) and the maximal plasma concentration (C max) rose in proportion to the dose over the 20 to 240 mg range (that is, 0.25 to 3 times the recommended dosage). The pharmacokinetics (PK) were linear. Taken orally once daily, osimertinib built up about 3-fold in the body, and steady state exposure was reached after 15 days of dosing. At steady state, the C max to C min (minimal concentration) ratio was 1.6-fold.

Absorption: the median time to C max was 6 hours (range 3 to 24 hours). When a 20 mg tablet was given with a high-fat, high-calorie meal (about 58 grams of fat and 1000 calories), the C max and AUC were compared with those under fasting conditions.

Distribution: the mean volume of distribution at steady state (Vss/F) was 986 L. Plasma protein binding was 95%.

Elimination: plasma concentrations fell with time. The population estimated mean half-life was 48 hours, and oral clearance (CL/F) was 14.2 (L/h).

Metabolism: in vitro, the main metabolic pathways were oxidation (predominantly CYP3A) and dealkylation. The two active metabolites, AZ7550 and AZ5104, were found in plasma after oral use. At steady state, the geometric mean exposure (AUC) of each one was about 10% of the exposure to osimertinib.

Excretion: osimertinib is eliminated mainly in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib made up about 2% of the elimination.

Osimertinib can cause harm to the baby if a pregnant woman takes it. There are no data on its use in pregnant women. There are also no data on whether Osimertinib passes into human milk, what it does to a breastfed infant, or whether it affects milk production.

Contraception

Women who could become pregnant should be advised to use effective contraception during treatment with Osimertinib and for 6 weeks after the final dose. Men who have female partners able to become pregnant should be advised to use effective contraception during treatment and for 4 months after the final dose.

Infertility

Animal studies suggest that Osimertinib may impair fertility in women and men who are able to have children. The effects on female fertility showed a trend toward reversibility. It isn't known whether the effects on male fertility can be reversed.

Age, sex, ethnicity, body weight, baseline albumin, line of therapy and smoking status made no clinically significant difference to the pharmacokinetics of Osimertinib. The same was true for mild (ClCr 60-89 ml/min), moderate (ClCr 30-59 ml/min, as estimated by C-G) or severe (ClCr 15-29 ml/min) renal impairment. It was also true for mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin between 1 to 1.5 times ULN and any AST) and moderate hepatic impairment (total bilirubin between 1.5 to 3 times ULN and any AST). In patients with end-stage renal disease (ClCr <15 ml/min) or severe hepatic impairment (total bilirubin between 3 to 10 times ULN and any AST), the pharmacokinetics of Osimertinib are unknown.

Pediatric use: the safety and effectiveness of Osimertinib in pediatric patients have not been established.

Geriatric use: no overall differences in effectiveness were seen based on age. Exploratory analysis suggests that patients 65 years or older had a higher incidence of Grade 3 and 4 adverse reactions (32% versus 25%) than those younger than 65 years. They also had more frequent dose modifications for adverse reactions (13.4% versus 9.3%), and again more frequent dose modifications for adverse reactions (13.4% versus 7.6%).

Renal impairment: no dose adjustment is recommended in patients with mild, moderate or severe renal impairment. There is no recommended dose of Osimertinib for patients with end-stage renal disease.

Hepatic impairment: there is no recommended dose for patients with severe hepatic impairment.

Keep Osimertinib below 30°C and protect it from moisture and light. If any medicine is out of date or you no longer need it, throw it away safely. Keep Osimertinib, like all medicines, out of the reach of children.