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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.
Transplantation. 2003 Oct 15; 76(7):1079-84.T

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.

Authors+Show Affiliations

Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX, USA. barry.d.kahan@uth.tmc.edu.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase I
Journal Article
Multicenter Study
Randomized Controlled Trial

Language

eng

PubMed ID

14557756

Citation

Kahan, Barry D., et al. "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, 2003, pp. 1079-84.
Kahan BD, Karlix JL, Ferguson RM, et al. Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: a multicenter, randomized, placebo-controlled, phase I study. Transplantation. 2003;76(7):1079-84.
Kahan, B. D., Karlix, J. L., Ferguson, R. M., Leichtman, A. B., Mulgaonkar, S., Gonwa, T. A., Skerjanec, A., Schmouder, R. L., & 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, 76(7), 1079-84.
Kahan BD, et al. Pharmacodynamics, Pharmacokinetics, and Safety of Multiple Doses of FTY720 in Stable Renal Transplant Patients: a Multicenter, Randomized, Placebo-controlled, Phase I Study. Transplantation. 2003 Oct 15;76(7):1079-84. PubMed PMID: 14557756.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacodynamics, pharmacokinetics, and safety of multiple doses of FTY720 in stable renal transplant patients: 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/pubmed PY - 2003/12/3/medline PY - 2003/10/15/entrez SP - 1079 EP - 84 JF - Transplantation JO - Transplantation VL - 76 IS - 7 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. SN - 0041-1337 UR - https://www.unboundmedicine.com/medline/citation/14557756/Pharmacodynamics_pharmacokinetics_and_safety_of_multiple_doses_of_FTY720_in_stable_renal_transplant_patients:_a_multicenter_randomized_placebo_controlled_phase_I_study_ L2 - http://dx.doi.org/10.1097/01.TP.0000084822.01372.AC DB - PRIME DP - Unbound Medicine ER -