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. 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.