Effect of food on everolimus absorption: quantification in healthy subjects and a confirmatory screening in patients with renal transplants.
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.
Kovarik
John M
JM
Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@pharma.novartis.com
Hartmann
Stefan
S
Figueiredo
Joaquim
J
Rordorf
Christiane
C
Golor
Georg
G
Lison
Arno
A
Budde
Klemmens
K
Neumayer
Hans H
HH
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
D004041:Dietary Fats; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D011241:Prednisone; D020123:Sirolimus