Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Abstract

Preclinical and clinical studies were conducted to determine the metabolism and pharmacokinetics of osimertinib and key metabolites AZ5104 and AZ7550. Osimertinib was designed to covalently bind to epidermal growth factor receptors, allowing it to achieve nanomolar cellular potency . Covalent binding was observed in incubations of radiolabeled osimertinib with human and rat hepatocytes, human and rat plasma, and human serum albumin. Osimertinib, AZ5104, and AZ7550 were predominantly metabolized by CYP3A. Seven metabolites were detected in human hepatocytes, also observed in rat or dog hepatocytes at similar or higher levels. After oral administration of radiolabeled osimertinib to rats, drug-related material was widely distributed, with the highest radioactivity concentrations measured at 6 hours postdose in most tissues; radioactivity was detectable in 42% of tissues 60 days postdose. Concentrations of [ 14 C]-radioactivity in blood were lower than in most tissues. After the administration of a single oral dose of 20 mg of radiolabeled osimertinib to healthy male volunteers, ∼19% of the dose was recovered by 3 days postdose. At 84 days postdose, mean total radioactivity recovery was 14.2% and 67.8% of the dose in urine and feces. The most abundant metabolite identified in feces was AZ5104 (∼6% of dose). Osimertinib accounted for ∼1% of total radioactivity in the plasma of non-small cell lung cancer patients after 22 days of 80-mg osimertinib once-daily treatment; the most abundant circulatory metabolites were AZ7550 and AZ5104 (<10% of total osimertinibrelated material). Osimertinib is extensively distributed and metabolized in humans and is eliminated primarily via the fecal route.

Identification of Novel Pathways of Osimertinib Disposition and Potential Implications for the Outcome of Lung Cancer Therapy

“…Indeed, recombinant CYP2A6 did not produce this metabolite (Figure 2A). It should be noted however that Dickinson et al observed some activity of recombinant CYP2A6 with osimertinib (26). Formation of DM-2 in the HLM panel agreed less well with the recombinant protein data, as correlation with CYP3A4 activity was considerably weaker than with CYP2A6, CYP2B6 and CYP2C8.…”

“…In humans, CYP3A enzymes have been reported to be primarily responsible for both the generation and the further metabolism of the key active metabolites, DM-1 (AZ5104) and DM-2 (AZ7550) (25,26,31). In the humanized model exposure to DM-1 decreased to a similar extent in both mouse lines after RIF pre-treatment (Figure 4C,D).…”

Absolute Bioavailability of Osimertinib in Healthy Adults

“…21,23 A single oral dose of osimertinib was slowly absorbed, and after C max , concentrations declined in a monophasic manner. The oral absolute bioavailability of an 80mg single oral dose of osimertinib in healthy subjects was 69.8%, suggesting that osimertinib is well absorbed in humans.…”

“…Two active metabolites, AZ5104 and AZ7550, 22 circulate at approximately 10% of osimertinib exposure at steady state. 23 Of the excreted radioactivity, unchanged osimertinib constitutes approximately 1.2% in feces and 0.71% in urine (in samples up to 7 days postdose) indicating that the majority of the elimination occurs via metabolism. 23 Of the excreted radioactivity, unchanged osimertinib constitutes approximately 1.2% in feces and 0.71% in urine (in samples up to 7 days postdose) indicating that the majority of the elimination occurs via metabolism.…”

“…21 After oral dosing, osimertinib is mainly eliminated in feces (67.8%, 84 days postdose), with urinary elimination accounting for 14.2%. 23 However, the absolute bioavailability of osimertinib has not been reported. 23 However, the absolute bioavailability of osimertinib has not been reported.…”