Ketoconazole

The coadministration of ketoconazole (a potent inhibitor of CYP3A and CYP4F) 200 mg twice daily at steady-state and a single dose of fingolimod 5 mg led to a 70% increase in AUC of fingolimod and fingolimod-phosphate.  Patients who use GILENYA and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater. [See Drug Interaction s (7)].  

Potential of fingolimod and fingolimod-phosphate to inhibit the metabolism of co-medications

In vitro inhibition studies in pooled human liver microsomes and specific metabolic probe substrates demonstrate that fingolimod has little or no capacity to inhibit the activity of the following CYP450 enzymes: CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A9/11, and similarly fingolimod-phosphate has little or no capacity to inhibit the activity of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 at concentrations up to three orders of magnitude of therapeutic concentrations. Therefore, fingolimod and fingolimod-phosphate are unlikely to reduce the clearance of drugs that are mainly cleared through metabolism by the major cytochrome P450 isoenzymes described above. The potential of fingolimod to inhibit CYP2C8 and fingolimod-phosphate to inhibit CYP2B6 is unknown. 

Potential of fingolimod and fingolimod-phosphate to induce its own and/or the metabolism of co-medications

Fingolimod was examined for its potential to induce human CYP3A4, CYP1A2, CYP4F2, and MDR1 (P-glycoprotein) mRNA and CYP3A, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP4F2 activity in primary human hepatocytes. Fingolimod did not induce mRNA or activity of the different CYP450 enzymes and MDR1 with respect to the vehicle control; therefore, no clinically relevant induction of the tested CYP450 enzymes or MDR1 by fingolimod are expected at therapeutic concentrations. The potential of fingolimod-phosphate to induce CYP450 isoenzymes is unknown.

Transporters

Fingolimod as well as fingolimod-phosphate are not expected to inhibit the uptake of co-medications and/or biologics transported by OATP1B1, OATP1B3, or NTCP. Similarly, they are not expected to inhibit the efflux of co-medications and/or biologics transported by the breast cancer resistant protein (MXR), the bile salt export pump (BSEP), the multidrug resistance-associated protein 2 (MRP2), and MDR1-mediated transport at therapeutic concentrations.

Cyclosporine

The pharmacokinetics of single-dose fingolimod were not altered during coadministration with cyclosporine at steady-state, nor was cyclosporine steady-state pharmacokinetics altered by fingolimod. These data indicate that GILENYA is unlikely to reduce the clearance of drugs mainly cleared by CYP3A4 and show that the potent inhibition of transporters MDR1, MRP2, and OATP-C does not influence fingolimod disposition.

Isoproterenol, atropine, atenolol, and diltiazem

Single-dose fingolimod and fingolimod-phosphate exposure was not altered by coadministered isoproterenol or atropine. Likewise, the single-dose pharmacokinetics of fingolimod and fingolimod-phosphate and the steady-state pharmacokinetics of both atenolol and diltiazem were unchanged during the coadministration of the latter two drugs individually with fingolimod.

Population pharmacokinetics analysis

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