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Effect of Food on Everolimus Absorption: Quantification in Healthy Subjects and a Confirmatory Screening in Patients with Renal Transplants
Author(s) -
Kovarik John M.,
Hartmann Stefan,
Figueiredo Joaquim,
Rordorf Christiane,
Golor Georg,
Lison Arno,
Budde Klemmens,
Neumayer Hans H.
Publication year - 2002
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1592/phco.22.3.154.33542
Subject(s) - everolimus , medicine , cmax , meal , crossover study , pharmacokinetics , urology , placebo , bioavailability , hibiscus sabdariffa , area under the curve , dosing , gastroenterology , pharmacology , pathology , alternative medicine , traditional medicine
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 (T max ) by a median 1.25 hours, reduced peak blood concentration (C max ) 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 (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.