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Ketoconazole Increases Fingolimod Blood Levels in a Drug Interaction via CYP4F2 Inhibition
Author(s) -
Kovarik John M.,
Dole Kiran,
Riviere GillesJacques,
Pommier Francoise,
Maton Steve,
Jin Yi,
Lasseter Kenneth C.,
Schmouder Robert L.
Publication year - 2009
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270008329553
Subject(s) - ketoconazole , fingolimod , pharmacology , pharmacokinetics , drug interaction , active metabolite , medicine , crossover study , placebo , immunology , antifungal , multiple sclerosis , alternative medicine , pathology , dermatology
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.