Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients

A multicenter, randomized, placebo-controlled, phase I study

Barry D. Kahan, Janet L. Karlix, Ronald M. Ferguson, Alan B. Leichtman, Shamkant Mulgaonkar, Thomas A. Gonwa, Andrej Skerjanec, Robert L. Schmouder, Lawrence Chodoff

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1079-1084
Number of pages6
JournalTransplantation
Volume76
Issue number7
DOIs
StatePublished - Oct 15 2003

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Pharmacokinetics
Placebos
Transplants
Kidney
Safety
Cyclosporine
Prednisone
Fingolimod Hydrochloride
Lymphocyte Count
Immunologic Factors
Immunosuppressive Agents
Bradycardia
Kidney Transplantation
Lymphocytes
Incidence
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Transplantation
  • Immunology

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Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients : A multicenter, randomized, placebo-controlled, phase I study. / Kahan, Barry D.; Karlix, Janet L.; Ferguson, Ronald M.; Leichtman, Alan B.; Mulgaonkar, Shamkant; Gonwa, Thomas A.; Skerjanec, Andrej; Schmouder, Robert L.; Chodoff, Lawrence.

In: Transplantation, Vol. 76, No. 7, 15.10.2003, p. 1079-1084.

Research output: Contribution to journalArticle

Kahan, BD, Karlix, JL, Ferguson, RM, Leichtman, AB, Mulgaonkar, S, Gonwa, TA, Skerjanec, A, Schmouder, RL & Chodoff, L 2003, 'Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: A multicenter, randomized, placebo-controlled, phase I study', Transplantation, vol. 76, no. 7, pp. 1079-1084. https://doi.org/10.1097/01.TP.0000084822.01372.AC
Kahan, Barry D. ; Karlix, Janet L. ; Ferguson, Ronald M. ; Leichtman, Alan B. ; Mulgaonkar, Shamkant ; Gonwa, Thomas A. ; Skerjanec, Andrej ; Schmouder, Robert L. ; Chodoff, Lawrence. / Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients : A multicenter, randomized, placebo-controlled, phase I study. In: Transplantation. 2003 ; Vol. 76, No. 7. pp. 1079-1084.
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abstract = "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.",
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T1 - Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients

T2 - A multicenter, randomized, placebo-controlled, phase I study

AU - Kahan, Barry D.

AU - Karlix, Janet L.

AU - Ferguson, Ronald M.

AU - Leichtman, Alan B.

AU - Mulgaonkar, Shamkant

AU - Gonwa, Thomas A.

AU - Skerjanec, Andrej

AU - Schmouder, Robert L.

AU - Chodoff, Lawrence

PY - 2003/10/15

Y1 - 2003/10/15

N2 - 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.

AB - 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.

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