title: Effect of food on everolimus absorption: quantification in healthy subjects and a confirmatory screening in patients with renal transplants.
abstract: 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.
  
  
  METHODS
  Randomized, open-label, crossover, single-dose study and confirmatory screening.
  
  
  METHODS
  Phase 1 unit for the single-dose study and two German hospitals for the patient screening.
  
  
  METHODS
  Twenty-four healthy male volunteers; six clinically stable patients with renal transplants who were originally part of a phase I dose-escalation study.
  
  
  METHODS
  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.
  
  
  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.
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@pharma.novartis.com
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Stefan
authors.initials: S
authors.lastname: Hartmann
authors.forename: Joaquim
authors.initials: J
authors.lastname: Figueiredo
authors.forename: Christiane
authors.initials: C
authors.lastname: Rordorf
authors.forename: Georg
authors.initials: G
authors.lastname: Golor
authors.forename: Arno
authors.initials: A
authors.lastname: Lison
authors.forename: Klemmens
authors.initials: K
authors.lastname: Budde
authors.forename: Hans H
authors.initials: HH
authors.lastname: Neumayer
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000493:pharmacokinetics; D004041:Dietary Fats / Q000494:pharmacology*; D004347:Drug Interactions; D000068338:Everolimus; D005215:Fasting / Q000097:blood; D006207:Half-Life; D006261:Headache / Q000139:chemically induced; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008875:Middle Aged; D011241:Prednisone / Q000493:pharmacokinetics; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D013997:Time Factors
chemical_list: D004041:Dietary Fats; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D011241:Prednisone; D020123:Sirolimus