Blood Concentrations of Everolimus Are Markedly Increased by Ketoconazole

The authors sought to quantify the influence of the CYP3A and P‐glycoprotein inhibitor ketoconazole on the pharmacokinetics of everolimus in healthy subjects. This was a 2‐period, single‐sequence, crossover study in 12 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 ketoconazole 200 mg twice daily for a total of 8 days and a single dose of everolimus coadministered on the fourth day of ketoconazole therapy. The test/reference ratio and 90% confidence interval were derived for everolimus maximum concentration and area under the curve. During ketoconazole coadministration, everolimus maximum concentration increased 3.9‐fold (90% confidence interval, 3.4–4.6) from 15 ± 4 ng/mL to 59 ± 13 ng/mL. Everolimus area under the curve increased 15.0‐fold (90% confidence interval, 13.6–16.6) from 90 ± 23 ng•h/mL to 1324 ± 232 ng•h/mL. Everolimus half‐life was prolonged by 1.9‐fold from 30 ± 4 hours to 56 ± 5 hours. Everolimus did not appear to alter ketoconazole predose concentrations. Given the magnitude of this drug interaction, use of ketoconazole should be avoided if possible in everolimus‐treated patients.