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DRUG INTERACTIONS

FTY720 and Cyclosporine: Evaluation for a Pharmacokinetic Interaction

Clinical Pharmacologist, Novartis Pharma, Basel, Switzerland

Robert L Schmouder, MD

Clinical Pharmacologist, Novartis Pharmaceuticals, East Hanover, NJ

Denise Barilla

Clinical Pharmacology Research Scientist, Novartis Pharmaceuticals, East Hanover

Monika Büche

Clinical Pharmacology Research Scientist, Novartis Pharma, Basel

Marisel Rouilly, Dr. Rer. Nat.

Bioanalyst, Novartis Pharma, Basel

Stephane Berthier, PharmD

Bioanalyst, Novartis Pharma, Basel

Yibin Wang, PhD

Biostatistician, Novartis Pharmaceuticals, East Hanover

Claudia Van Saders, RN

Study Nurse, Clinical Research Center, University of Medicine and Dentistry of New Jersey (UMDNJ)–Robert Wood Johnson Medical School, New Brunswick, NJ

Thomas Mayer, MD

Physician, Institute for Clinical Pharmacology, Grünstadt, Germany

Alice B Gottlieb, MD PhD

Professor of Medicine, Clinical Research Center, UMDNJ–Robert Wood Johnson Medical School

Reprints: John M Kovarik PhD, Novartis Pharmaceuticals, Building WSJ 27.3104, 4002 Basel, Switzerland, fax 41 061 324 2959, john.kovarik{at}pharma.novartis.com

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 (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.

Key Words: cyclosporine, drug interactions, FTY720, immunosuppressants

Published Online, May 11, 2004. www.theannals.com, DOI 10.1345/aph.1E035

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