Ketoconazole increases fingolimod blood levels in a drug interaction via CYP4F2 inhibition

J Clin Pharmacol. 2009 Feb;49(2):212-8. doi: 10.1177/0091270008329553. Epub 2008 Dec 31.


The sphingosine-1-phosphate receptor modulator fingolimod is predominantly hydroxylated by cytochrome CYP4F2. In vitro experiments showed that ketoconazole significantly inhibited the oxidative metabolism of fingolimod by human liver microsomes and by recombinant CYP4F2. The authors used ketoconazole as a putative CYP4F2 inhibitor to quantify its influence on fingolimod pharmacokinetics in healthy subjects. In a 2-period, single-sequence, crossover study, 22 healthy subjects received a single 5-mg dose of fingolimod in period 1. In period 2, subjects received ketoconazole 200 mg twice daily for 9 days and a single 5-mg dose of fingolimod coadministered on the 4th day of ketoconazole treatment. Ketoconazole did not affect fingolimod t(max) or half-life, but there was a weak average increase in C(max) of 1.22-fold (90% confidence interval, 1.15-1.30). The AUC over the 5 days of ketoconazole coadministration increased 1.40-fold (1.31-1.50), and the full AUC to infinity increased 1.71-fold (1.53-1.91). The AUC of the active metabolite fingolimod-phosphate was increased to a similar extent by 1.67-fold (1.50-1.85). Ketoconazole predose plasma levels were not altered by fingolimod. The magnitude of this interaction suggests that a proactive dose reduction of fingolimod is not necessary when adding ketoconazole to a fingolimod regimen. The clinician, however, should be aware of this interaction and bear in mind the possibility of a fingolimod dose reduction based on clinical monitoring.

Publication types

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

MeSH terms

  • Adult
  • Antifungal Agents / pharmacokinetics
  • Antifungal Agents / pharmacology
  • Area Under Curve
  • Cross-Over Studies
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 4
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Monitoring
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fingolimod Hydrochloride
  • Half-Life
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacokinetics*
  • Immunosuppressive Agents / pharmacology
  • Ketoconazole / pharmacokinetics
  • Ketoconazole / pharmacology*
  • Male
  • Middle Aged
  • Propylene Glycols / administration & dosage
  • Propylene Glycols / pharmacokinetics*
  • Propylene Glycols / pharmacology
  • Sphingosine / administration & dosage
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacokinetics
  • Sphingosine / pharmacology
  • Young Adult


  • Antifungal Agents
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Immunosuppressive Agents
  • Propylene Glycols
  • Cytochrome P-450 Enzyme System
  • Cytochrome P450 Family 4
  • CYP4F2 protein, human
  • Fingolimod Hydrochloride
  • Sphingosine
  • Ketoconazole