title: Pharmacokinetics of the immunosuppressant everolimus in maintenance renal transplant patients.
abstract: The novel macrocyclic immunosuppressant everolimus has been approved for use in renal and heart transplantation. The objective of this randomized, double-blind, placebo-controlled, dose-escalating Phase 1 study was to evaluate the pharmacokinetic profile of different dosing regimens of everolimus. Fifty-four subjects were randomized for 4-weeks treatment with everolimus (n = 44) or placebo (n = 10). Steady state was reached by day 4 of multiple dosing with evidence for dose-proportionality over the dose range tested. Systemic accumulation was 1.6- to 2.2-fold with multiple dosing. Steady-state predose trough concentrations were well correlated with AUC (r = 0.87, p < 0.001). Within-subject coefficients of variation for the tablet formulation ranged from 10-19% and between-subject coefficients from 34-60% for Cmax and AUC. There was no effect of common demographic parameters (age, sex, weight) on variability in steady-state exposure. These results support the clinical use of everolimus in renal transplantation.
authors.affiliation: Department of Nephrology, Charité University Hospital, Schumannstr. 20-21, D-10117 Berlin, Germany. klemens.budde@charite.de
authors.forename: K
authors.initials: K
authors.lastname: Budde
authors.forename: L
authors.initials: L
authors.lastname: Fritsche
authors.forename: J
authors.initials: J
authors.lastname: Waiser
authors.forename: P
authors.initials: P
authors.lastname: Glander
authors.forename: T
authors.initials: T
authors.lastname: Slowinski
authors.forename: H-H
authors.initials: HH
authors.lastname: Neumayer
mesh_terms: D019540:Area Under Curve; D001682:Biological Availability; D015331:Cohort Studies; D003710:Demography; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008657:Metabolic Clearance Rate; D010919:Placebos; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D010919:Placebos; D000068338:Everolimus; D020123:Sirolimus