Pharmacokinetic (PK) profile of a single dose of everolimus (10 mg) administered with a low- or high-fat meal and under fasting conditions in healthy subjects.

e15080 Background: The mTOR inhibitor everolimus is approved for patients (pts) with metastatic renal cell carcinoma after failure of sunitinib or sorafenib, and for pts with subependymal giant-cell astrocytoma associated with tuberous sclerosis who require therapeutic intervention but are not candidates for curative surgery. Studies in healthy subjects suggest that systemic exposure to everolimus is reduced with a high-fat meal. The effect of fasting conditions and food on everolimus PK after an oral 10 mg dose was evaluated. Methods: In this single-center, open-label study, 24 healthy male and female subjects were randomized to single doses of everolimus in a 3-treatment (low-fat vs high-fat meal vs fasting), 3-period, 6-sequence crossover design. Treatment periods were separated by 14-day washout intervals. PK was assessed at baseline and at 0-12, 24, 36, 48, 72, 96, 120, and 144 hours postdose. Results: All 24 subjects were included in the PK analysis. The geometric mean Cmax decreased by 42% after a low-fat meal and by 54% after a high-fat meal compared with fasting conditions. Total exposure (geometric mean AUC0-t and AUC0-∞) decreased by 22% to 33% after intake of a low- or high-fat meal. A meal had no apparent effect on the post-absorption concentration-time profile. The gastrointestinal absorption rate of everolimus was decreased by food intake: median Tmax was 1 hour in the fasted state, 1.75 hours after a low-fat meal, and 2.50 hours after a high-fat meal. The elimination kinetics in whole blood (T1/2 [35.6 to 40.9 hours] and mean residence time [29.2 to 32.2 hours]) did not appear to be affected by food intake regardless of fasting or nonfasting state. No deaths, serious adverse events (AEs), or significant AEs were reported. Conclusions: The systemic availability of a single oral 10 mg dose of everolimus is significantly reduced by coadministration with a meal (low or high fat) compared with fasting conditions; however, food is not expected to have clinically significant effects on predose trough concentration during daily administration of everolimus. All conditions tested were safe and well tolerated.