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J Am Soc Nephrol 13:1073-1083, 2002
© 2002 American Society of Nephrology

First Human Trial of FTY720, a Novel Immunomodulator, in Stable Renal Transplant Patients

Klemens Budde*, Robert L. Schmouder{dagger}, Reinhard Brunkhorst{ddagger}, Bjorn Nashan§, Peter W. Lücker, Thomas Mayer, Somesh Choudhury{dagger}, Andrej Skerjanec{dagger}, Gerolf Kraus{dagger} and Hans H. Neumayer*

*University Hospital Charité, Department of Nephrology, Berlin, Germany; {dagger}Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; {ddagger}Oststadt Krankenhaus Hannover, Hannover, Germany; §Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.

Correspondence to: Dr. Klemens Budde, Charité University Hospital, Schumannstrasse 20-21, 10117 Berlin, Germany. Phone: 49-3045-051-4002; Fax: 49-3045-051-4900; E-mail: klemens.budde{at}charite.de

ABSTRACT. FTY720 is a novel immunomodulator to be developed for use in organ transplantation. The primary objective of this study was to measure safety, single-dose pharmacokinetics, and pharmacodynamics in stable renal transplant patients—the first human use of FTY720. This study used a randomized, double-blind, placebo-controlled design that explored single oral doses of FTY720 from 0.25 to 3.5 mg in 20 stable renal transplant patients on a cyclosporine-based regimen. Safety assessments and blood samples were taken predose and at multiple time points during a 96-h period postdose. Standard pharmacokinetic parameters were derived from the FTY720 whole blood concentrations, measured by HPLC/MS/MS. FTY720 was well tolerated, with no serious adverse events. Transient, asymptomatic bradycardia occurred after administration in 10 of 24 doses of FTY720. Pharmacokinetics are characterized by a prolonged absorption phase; the terminal elimination phase started 36 h after the administration, with elimination half-life (t1/2) ranging from 89 to 157 h independent of dose. Maximum plasma concentration and AUC were proportional to dose with low intersubject variability, the apparent volume of distribution (Vd/F) ranged from 1116 to 1737 L. FTY pharmacodynamics were characterized by a reversible transient lymphopenia within 6 h, the nadir being 42% of baseline. The lymphocyte count returned to baseline within 72 h in all dosing cohorts except the highest. Single oral doses of FTY720 ranging from 0.25 to 3.5 mg were well tolerated and caused a reversible selective lymphopenia. Transient, but asymptomatic bradycardia was the most common adverse event. The long t1/2 suggests less frequent dosing intervals. The size of Vd/F is in excess of blood volume, consistent with widespread tissue distribution




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