title: First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients.
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 (t(1/2)) 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 (V(d)/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 t(1/2) suggests less frequent dosing intervals. The size of V(d)/F is in excess of blood volume, consistent with widespread tissue distribution
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schmouder
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Brunkhorst
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Nashan
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Lücker
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayer
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Somesh
authors.initials: S
authors.lastname: Choudhury
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Gerolf
authors.initials: G
authors.lastname: Kraus
authors.affiliation: *University Hospital Charité, Department of Nephrology, Berlin, Germany; Clinical Pharmacology and Drug Metabolism and Pharmacokinetics, Novartis Pharma, Basel, Switzerland and East Hanover, New Jersey; Oststadt Krankenhaus Hannover, Hannover, Germany; Medizinische Hochschule Hannover, Klinik fur Viszeral und Transplantationschirurgie, Hannover, Germany; Institute für Klinische Pharmakologie Bobenheim, Grüenstadt, Germany.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Neumayer
mesh_terms: D000328:Adult; D000681:Amylases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D000068876:Fingolimod Hydrochloride; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008049:Lipase / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011409:Propylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012129:Respiratory Function Tests; D013110:Sphingosine / Q000031:analogs & derivatives
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D008049:Lipase; D000681:Amylases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine