Blood concentrations of everolimus are markedly increased by ketoconazole

J Clin Pharmacol. 2005 May;45(5):514-8. doi: 10.1177/0091270005275368.

Abstract

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antifungal Agents / pharmacology*
  • Area Under Curve
  • Cross-Over Studies
  • Drug Synergism
  • Everolimus
  • Female
  • Half-Life
  • Humans
  • Immunosuppressive Agents / blood*
  • Immunosuppressive Agents / pharmacokinetics
  • Ketoconazole / pharmacology*
  • Male
  • Middle Aged
  • Sirolimus / analogs & derivatives*
  • Sirolimus / blood*
  • Sirolimus / pharmacokinetics

Substances

  • Antifungal Agents
  • Immunosuppressive Agents
  • Everolimus
  • Ketoconazole
  • Sirolimus