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 I 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 (Tmax) by a median 1.25 hours, reduced peak blood concentration (Cmax) by 60%, and reduced area under the concentration-time curve (AUC) by 16%. In the multiple-dose screening in patients with renal transplants, a high-fat meal delayed Tmax by a median 1.75 hours and reduced Cmax 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.