Effect of food on everolimus absorption: Quantification in healthy subjects and a confirmatory screening in patients with renal transplants

Study Objective. To quantify the influence of a high-fat meal on the oral bioavailability of the immunosuppressant everolimus in a single-dose study in healthy subjects and to confirm the results in a small food-effect screening assessment in patients with renal transplants who were receiving multiple-dose everolimus. Design. Randomized, open-label, crossover, single-dose study and confirmatory screening. Setting. Phase 1 unit for the single-dose study and two German hospitals for the patient screening. Subjects. Twenty-four healthy male volunteers; six clinically stable patients with renal transplants who were originally part of a phase 1 dose-escalation study. Intervention. The 24 healthy men received everolimus 2 mg orally under fasting conditions and after a high-fat meal. The six patients received everolimus 2.5 mg/day orally, in addition to cyclosporine and prednisone. On two occasions, a pharmacokinetic profile was obtained over the dosing interval after drug administration under fasting conditions and after a high-fat meal in a randomized sequence. Measurements and Main Results. In the single-dose study in healthy subjects, a high-fat meal delayed everolimus time to maximum concentration (T-max) by a median 1.25 hours, reduced peak blood concentration (C-max) by 60%, and reduced area under the concentrationtime curve (AUC) by 16%. In the multiple-dose screening in patients with renal transplants, a high-fat meal delayed T-max by a median 1.75 hours and reduced C-max by 53% and AUC by 21%. Everolimus trough levels showed no food effect, whereas the peak-trough fluctuation was dampened by 52%. Conclusions. A high-fat meal modestly reduced everolimus AUC. To minimize longitudinal variability in exposure, everolimus should be administered consistently either with food or without food.