title: Exposure-efficacy relationships of a fingolimod-everolimus regimen in kidney transplant patients at risk for delayed graft function.
abstract: OBJECTIVE
  We explored relationships between blood levels of fingolimod (FTY720) and everolimus versus treated biopsy-proven acute rejection (BPAR) in an open-label trial in de novo kidney transplant recipients.
  
  
  METHODS
  Patients (n = 52) who fulfilled predefined criteria placing them at increased risk of delayed graft function received fingolimod 2.5 mg/d, everolimus 2 mg twice daily with trough blood levels (C0) adjusted to 4 to 8 ng/mL, and corticosteroids. Everolimus and fingolimod C0 were collected over 1 year; efficacy readout was at 3 months.
  
  
  RESULTS
  Fingolimod C0 accumulated over the first 3 months with a time-averaged level (C0avg) of 5.7 +/- 3.5 ng/mL. At steady state in months 3 to 12, C0 was 7.0 +/- 4.4 ng/mL. Overall, 30 patients (58%) were free from BPAR to month 3. Patients were divided into four groups based on whether their fingolimod C0avg and everolimus C0avg were above or below the population medians. Freedom from BPAR was 53% and 57% for low fingolimod combined with low and high everolimus, whereas the percentages were improved to 83% and 85% for high fingolimod combined with low and high everolimus.
  
  
  CONCLUSIONS
  This pilot study with an everolimus-fingolimod regimen demonstrated trends in freedom from rejection that were drug concentration-related and that underscored, in particular, a strong contribution to efficacy from fingolimod.
authors.affiliation: Department of Clinical Pharmacology, Novartis Pharma, Basel, Switzerland. john.kovarik@novartis.com
authors.forename: J M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: H
authors.initials: H
authors.lastname: Tedesco-Silva
authors.forename: M I
authors.initials: MI
authors.lastname: Lorber
authors.forename: C
authors.initials: C
authors.lastname: Foster
mesh_terms: D004359:Drug Therapy, Combination; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D018655:Lymphocyte Count; D011183:Postoperative Complications / Q000453:epidemiology; D011409:Propylene Glycols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068338:Everolimus; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine; D020123:Sirolimus