title: FTY720, a novel immunomodulator in de novo kidney transplant patients: pharmacokinetics and exposure-response relationship.
abstract: The pharmacokinetics, safety, and preliminary efficacy of FTY720, a novel immunomodulator, were examined in de novo renal transplant patients. Both noncompartmental and population methods were used to estimate pharmacokinetic estimates in the patients. The steady-state plasma concentrations of FTY720 increased in accordance with maintenance dose level, indicating linearity in clearance and volume of distribution over the 0.25- to 2.5-mg dose range. The pharmacokinetics of FTY720 in de novo renal transplant patients were characterized by the long terminal phase half-life of approximately 200 hours across doses, high volume of distribution (>3000 L), and low clearance (10.8 L/h). The intersubject variation of clearance was 55%, and the intrasubject variation of FTY720 concentrations was 28%. The population analysis revealed significant positive relationships between baseline alkaline phosphatase and clearance, as well as between baseline body weight on apparent volume of distribution. There was no relationship between FTY720 concentrations within a given FTY720 dose cohort and the rate of allograft rejection.
authors.affiliation: Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA. andrej.skerjanec@novartis.com
authors.forename: Andrej
authors.initials: A
authors.lastname: Skerjanec
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco
authors.forename: Hans-H
authors.initials: HH
authors.lastname: Neumayer
authors.forename: Edward
authors.initials: E
authors.lastname: Cole
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Chyi-Hung
authors.initials: CH
authors.lastname: Hsu
authors.forename: Robert
authors.initials: R
authors.lastname: Schmouder
mesh_terms: D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011409:Propylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016572:Cyclosporine; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine