Osimertinib

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.