Effect of multiple-dose erythromycin on everolimus pharmacokinetics.
OBJECTIVE
We sought to quantify the influence of the CYP3A inhibitor erythromycin on the pharmacokinetics of everolimus, a CYP3A substrate.


METHODS
This was a two-period, single-sequence, crossover study in 16 healthy subjects. In period 1, subjects received the reference treatment of a single 2-mg dose of everolimus. In period 2, they received the test treatment of erythromycin 500 mg three times daily for a total of 9 days and a single 2-mg dose of everolimus coadministered on the fifth day of erythromycin therapy. The test/reference ratio and 90% confidence interval (CI) were derived for everolimus C (max) and AUC.


RESULTS
During erythromycin coadministration, everolimus C (max) increased 2.0-fold (90% CI, 1.8-2.3) from 20+/-5 ng/ml to 40+/-10 ng/ml. Everolimus AUC increased 4.4-fold (90% CI, 3.5-5.4) from 116+/-37 ng h/ml to 524+/-225 ng h/ml. Everolimus half-life was prolonged by 39% from 32+/-6 h to 44+/-6 h. Erythromycin predose concentrations were not changed after single-dose administration of everolimus.


CONCLUSIONS
Multiple-dose erythromycin increased single-dose everolimus blood levels by an average 4.4-fold (range, 2.0-12.6). During erythromycin treatment, a compensatory everolimus dose reduction should be made guided by everolimus therapeutic drug monitoring.
Kovarik
J M
JM
Novartis Pharma, Building WSJ 27.P081, 4002 Basel, Switzerland. john.kovarik@pharma.novartis.com
Beyer
D
D
Bizot
M N
MN
Jiang
Q
Q
Shenouda
M
M
Schmouder
R L
RL
D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004917:Erythromycin / Q000008:administration & dosage / Q000494:pharmacology*; D000068338:Everolimus; D005260:Female; D006207:Half-Life; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D004917:Erythromycin; D000068338:Everolimus; D020123:Sirolimus