title: Association of Clinical Events With Everolimus Exposure in Kidney Transplant Patients Receiving Low Doses of Tacrolimus.
abstract: A key objective in the use of immunosuppression after kidney transplantation is to attain the optimal balance between efficacy and safety. In a phase 3b, multicenter, randomized, open-label, noninferiority study, the incidences of clinical events, renal dysfunction, and adverse events (AEs) were analyzed at 12 months in 309 de novo renal transplant recipients receiving everolimus (EVR), low-dose tacrolimus (LTac), and prednisone. Cox proportional hazard regression modeling was used to estimate the probability of clinical events at specified combinations of time-normalized EVR and Tac trough concentrations. At 12 months, the highest incidence of treated biopsy-proven acute rejection (tBPAR) and graft loss occurred most often in patients with EVR trough concentration <3 ng/mL (64.7% and 10.5%, respectively). At 1 month and 12 months, increasing EVR levels were associated with fewer tBPAR events (both p < 0.0001). Low estimated glomerular filtration rate (eGFR) and decreased eGFR occurred more often in patients with lower EVR and higher Tac levels. AEs were most often observed in patients with EVR levels <3 ng/mL. This study supports maintaining an EVR trough concentration of 3-8 ng/mL, when combined with LTac, to achieve balanced efficacy and safety in renal transplant recipients.
  
  
  BACKGROUND
  NCT01025817.
authors.affiliation: University of Utah, Salt Lake City, UT.
authors.forename: F
authors.initials: F
authors.lastname: Shihab
authors.affiliation: University of Southern California, Los Angeles, CA.
authors.forename: Y
authors.initials: Y
authors.lastname: Qazi
authors.affiliation: Barnabas Health, Livingston, NJ.
authors.forename: S
authors.initials: S
authors.lastname: Mulgaonkar
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ.
authors.forename: K
authors.initials: K
authors.lastname: McCague
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ.
authors.forename: D
authors.initials: D
authors.lastname: Patel
authors.affiliation: California Pacific Medical Center, San Francisco, CA.
authors.forename: V R
authors.initials: VR
authors.lastname: Peddi
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN.
authors.forename: D
authors.initials: D
authors.lastname: Shaffer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000453:epidemiology; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D011379:Prognosis; D012307:Risk Factors; D016559:Tacrolimus / Q000627:therapeutic use*; D066027:Transplant Recipients; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068338:Everolimus; D016559:Tacrolimus
keywords: calcineurin inhibitor: tacrolimus; clinical research/practice; immunosuppressant; immunosuppressive regimens; kidney transplantation/nephrology; mechanistic target of rapamycin (mTOR); mechanistic target of rapamycin: everolimus; minimization/withdrawal