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 Cmax compared with cyclosporine given alone (1452 +/- 308 vs 1376 +/- 149 ng/mL, respectively) or AUC(tau) (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.
Kovarik
John M
JM
Novartis Pharma, Basel, Switzerland. John.Kovarik@pharma.novartis.com
Schmouder
Robert L
RL
Barilla
Denise
D
Büche
Monika
M
Rouilly
Marisel
M
Berthier
Stephane
S
Wang
Yibin
Y
Van Saders
Claudia
C
Mayer
Thomas
T
Gottlieb
Alice B
AB
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D004347:Drug Interactions; D005260:Female; D000068876:Fingolimod Hydrochloride; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011409:Propylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists; D049312:Receptors, Lysophospholipid; D013110:Sphingosine / Q000031:analogs & derivatives
D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine