e 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
A population pharmacokinetics eva luation performed in MS patientsdid not provide evidence for a significant effect of fluoxetine and paroxetine (strong CYP2D6 inhibitors) and carbamazepine (potent enzyme inducer) on fingolimod or fingolimod-phosphatepre-dose concentrations. In addition, the following commonly co-prescribed substances had no clinically relevant effect (<20%) on fingolimod or fingolimod-phosphate pre-dose concentrations: baclofen, gabapentin, oxybutynin, amantadine, modafinil, amitriptyline, pregabalin, and corticosteroids.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Oral carcinogenicity studies of fingolimod were conducted in mice and rats. In mice, fingolimod was administered at oral doses of 0, 0.025, 0.25, and 2.5 mg/kg/day for up to 2 years. The incidence of malignant lymphoma was increased in males and females at the mid and high dose. The lowest dose tested (0.025 mg/kg/day) is less than the recommended human dose (RHD) of 0.5 mg/day on a body surface area (mg/m2) basis. I
