title: The pharmacokinetics of everolimus in de novo kidney transplant patients receiving tacrolimus: an analysis from the randomized ASSET study.
abstract: BACKGROUND
  Pharmacokinetic data regarding a drug-drug interaction between everolimus and tacrolimus are sparse.
  
  
  METHODS
  In a pharmacokinetic substudy of the randomized ASSET trial, 46 de novo kidney transplant patients receiving very low (1.5-3 ng/mL) or low (4-7 ng/mL) tacrolimus exposure after month 3, both with everolimus and steroids, provided area under the curve (AUC) concentration profiles at day 5 and months 1, 3, and 12.
  
  
  RESULTS
  At month 12, mean values for tacrolimus trough concentration (C0), peak concentration (Cmax), and AUC0-12 in the very low tacrolimus group were approximately half that in the low tacrolimus group, but everolimus dose, C0, Cmax, and AUC0-12 were virtually identical in both groups. In a cross-study comparison with data at months 1 and 3 from the pharmacokinetic substudy of the A2307 trial, in which patients received cyclosporine, mean values for everolimus C0, Cmax and AUC0-12 were similar to those in the ASSET trial but the everolimus dose needed to achieve similar exposure was 1.5- to 2-fold higher with concomitant tacrolimus versus cyclosporine.
  
  
  CONCLUSIONS
  Everolimus exposure is unaffected when tacrolimus exposure is down-titrated within the trough concentration range of 1.5-7 ng/mL. Higher doses of everolimus are needed to achieve a given exposure when combined with tacrolimus versus cyclosporine.
authors.affiliation: Unit of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, Netherlands.
authors.forename: Maarten H L
authors.initials: MH
authors.lastname: Christiaans
authors.affiliation: Department of Clinical Pharmacology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.affiliation: Servicio de Nefrología, Hospital del Mar, Barcelona, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Pascual
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016572:Cyclosporine / Q000008:administration & dosage; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D013256:Steroids / Q000008:administration & dosage; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D013256:Steroids; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus; D016559:Tacrolimus