Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study.
BACKGROUND
FTY720, a novel immunomodulator, displays potent immunosuppressive activity in a variety of preclinical transplant models. This study examined the safety, pharmacodynamics, and pharmacokinetics of multiple doses of FTY720 in stable renal transplant patients.


METHODS
This randomized, multicenter, double-blind, placebo-controlled, phase I study included adults who had been maintained on a regimen of cyclosporine A (CsA) microemulsion and prednisone (or its equivalent) for at least 1 year after renal transplantation. Patients received once-daily doses of 0.125, 0.25, 0.5, 1.0, 2.5, or 5.0 mg FTY720, or placebo for 28 days. After completion of study drug administration, the patients were monitored until day 56 by serial laboratory tests, clinical examinations, and recording of adverse events. The study includes 76 treatment courses (61 FTY720 and 15 placebo), with 65 patients enrolled once and 11 reenrolled.


RESULTS
FTY720 doses greater than or equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte count by up to 85%, which reversed within 3 days after discontinuation of study medication. Compared with placebo-treated patients, FTY720 subjects did not show a major increase in adverse events or a change in renal function. Pharmacokinetic measurements revealed that FTY720 displayed linear relations of doses and concentrations over a wide range, but had no effect on CsA exposure.


CONCLUSIONS
At doses up to 5.0 mg/day for 28 days, stable renal transplant patients treated with FTY720 in combination with CsA and prednisone displayed a dose-dependent, reversible decline in peripheral blood lymphocytes without an enhanced incidence of collateral toxicities, except possibly bradycardia.
Kahan
Barry D
BD
Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA. barry.d.kahan@uth.tmc.edu.
Karlix
Janet L
JL
Ferguson
Ronald M
RM
Leichtman
Alan B
AB
Mulgaonkar
Shamkant
S
Gonwa
Thomas A
TA
Skerjanec
Andrej
A
Schmouder
Robert L
RL
Chodoff
Lawrence
L
D000328:Adult; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D018655:Lymphocyte Count; D008875:Middle Aged; D010919:Placebos; D011241:Prednisone / Q000627:therapeutic use; D011409:Propylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D013110:Sphingosine / Q000031:analogs & derivatives
D007166:Immunosuppressive Agents; D010919:Placebos; D011409:Propylene Glycols; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D011241:Prednisone