cally active metabolites (AZ7550 and AZ5104) have been identified in the plasma after TAGRISSO oral administration. The geometric mean exposure (AUC) of each metabolite (AZ5104 and AZ7550) was approximately 10% of the exposure of osimertinib at steady-state.
Excretion
Osimertinib is primarily eliminated in the feces (68%) and to a lesser extent in the urine (14%). Unchanged osimertinib accounted for approximately 2% of the elimination.
Specific Populations
No clinically significant differences in the pharmacokinetics of osimertinib were observed based on age, sex, ethnicity, body weight, smoking status, mild (CLcr 60-89 mL/min) or moderate (CLcr 30-59 mL/min) renal impairment, or mild hepatic impairment (total bilirubin <ULN and AST between 1 to 1.5x ULN or total bilirubin between 1.0 to 1.5 times ULN and any AST ). There are no data on the pharmacokinetics of osimertinib in patients with severe renal impairment (CLcr less than 30 mL/min) or with moderate to severe hepatic impairment (moderate: total bilirubin between 1.5 to 3.0 times ULN and any AST, and severe: total bilirubin between 3.0-10 times ULN and any AST).
Drug Interactions
Effect of Other Drugs on TAGRISSO:
Strong CYP3A Inhibitors: Clinical studies eva luating TAGRISSO in the presence of strong CYP3A inhibitors have not been conducted [see Drug Interactions (7.1)].
Strong CYP3A Inducers: Clinical studies eva luating TAGRISSO in the presence of strong CYP3A inducers have not been conducted [see Drug Interactions (7.1)].
Gastric Acid Reducing Agents: The exposure of osimertinib was not affected by concurrent administration of a single 80 mg TAGRISSO tablet following 40 mg omeprazole administration for 5 days.
Effect of Osimertinib on Other Drugs:
CYP450 Metabolic Pathways: Osimertinib is a competitive inhibitor of CYP3A, but not CYP2C8, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 2E1 in vitro. Osimertinib induced CYP3A4 (Pregnane X dependent) and CYP1A2 enzymes.
Transporter Systems: Based on in vitro studies, osimertinib is a substrate of P-glycoprotein and BCRP and is not a substrate of OATP1B1 and OATP1B3. Osimertinib is an inhibitor of BCRP and does not inhibit P-glycoprotein, OAT1, OAT3, OATP1B1, OATP1B3, MATE1, MATE2K and OCT2 in vitro.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies have not been performed with osimertinib. Osimertinib did not cause genetic damage in in vitro and in vivo assays.
Based on studies in animals, male fertility may be impaired by treatment with TAGRISSO. Degenerative changes were present in the testes in rats and dogs exposed to osimertinib for 1 month or more with evidence of reversibility in the rat. Following administration of osimertinib to rats for approximately 10 weeks at a dose of 40 mg/kg, at exposures 0.5-times the AUC observed in patients at the recommended dose of 80 mg, there was a reduction in male fertility, demonstrated by increased pre-implantation loss in untreated females mated to treated males.
Nonclinical female fertility studies have not been conducted. In repeat dose toxicity studies, histological evidence of anestrus, corpora lutea degeneration in the ovaries and epithelial thinning in the uterus and vagina were seen in rats exposed to osimertinib for 1 month or more at exposures 0.3-times the AUC observed in patients at the recommended dose of 80 mg. Findings in the ovaries seen following 1 month of dosing exhibited evidence of reversibility.
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