FTY720 and cyclosporine: Evaluation for a pharmacokinetic interaction

BACKGROUND: FTY720 is a sphingosine-1-phosphate receptor agonist intended for use in immunoprophylaxis regimens to prevent acute rejection after organ transplantation. OBJECTIVE: To evaluate the potential for a pharmacokinetic drug interaction between the immunomodulator FTY720 and cyclosporine to support the use of this drug combination in organ transplantation. METHODS: In this open-label, randomized crossover study, 12 subjects with psoriasis received a single dose of FTY720 1 mg alone and on day 5 of an 8-day course of cyclosporine 200 mg twice daily. The single-dose pharmacokinetics of FTY720 and the steady-state pharmacokinetics of cyclosporine were characterized when given alone and during coadministration. Routine safety data were collected, with special attention to total blood lymphocyte counts and heart rate. RESULTS: Cyclosporine coadministration compared with FTY720 given alone did not significantly alter FTY720 maximum concentration (C_max) (0.57 ± 0.17 vs 0.58 ± 0,19 · ng/mL, respectively) or AUC _0.t (41 ± 13 vs 41 ± 13 ng · h/mL, respectively). Likewise for cyclosporine, FTY720 coadministration did not alter the steady-state C_max compared with cyclosporine given alone (1452 ± 308 vs 1376 ± 149 ng/mL, respectively) or AUC_τ (6385 ± 1578 vs 6031 ± 1051 ng · h/mL, respectively). Mean lymphocyte counts decreased from baseline by an average of 35% over the first 2 days after FTY720 administration and thereafter increased to prestudy values by day 5 similarly in the absence and presence of cyclosporine. The morning mean supine heart rate decreased approximately 10% and returned to prestudy rates by day 5 after administration of FTY720 alone and with cyclosporine. Heart rate changes were asymptomatic in all study participants. One subject experienced asymptomatic second-degree type 1 atrioventricular (Wenckebach) block. CONCLUSIONS: The pharmacokinetics of single-dose FTY720 and steady-state cyclosporine were not altered during coadministration.