wever AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.
Dose Proportionality in Patients with SEGA and TSC: In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.
Food effect: In healthy subjects, high-fat meals reduced systemic exposure to AFINITOR 10 mg tablet (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light-fat meals reduced AUC by 32% and Cmax by 42%.
In healthy subjects who received 9 mg of AFINITOR DISPERZ, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and Cmax by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and Cmax by 50%.
Relative bioavailability of AFINITOR DISPERZ (everolimus tablets for oral suspension): The AUC0-∞ of AFINITOR DISPERZ was equivalent to that of AFINITOR Tablets; the Cmax of this dosage form was 20%-36% lower than that of AFINITOR Tablets. The predicted trough concentrations at steady-state were similar after daily administration.
Distribution
The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.
Metabolism
Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.
In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan.
Elimination
No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces. The mean elimination half-life of everolimus is approximately 30 hours.
Patients with Renal Impairment
Approximately 5% of total radioactivity was excreted in the urine following a 3 mg dose of [14C]-labeled everolimus. In a population pharmacokinetic analysis which included 170 patients with advanced cancer, no significant influence of creatinine clearance (25–178 mL/min) was detected on oral clearance (CL/F) of everolimus [see Use in Specific Populations (8.7)].
Patients with Hepatic Impairment
The safety, tolerability and pharmacokinetics of AFINITOR were eva luated in a single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Compared to normal subjects (N=13), there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in exposure (i.e. AUC) for subjects with mild (Child |
