title: Effects of calcineurin inhibitors on sirolimus pharmacokinetics during staggered administration in renal transplant recipients.
abstract: OBJECTIVE
  To compare the effects of different calcineurin inhibitors on sirolimus pharmacokinetics during long-term, staggered administration in kidney transplant recipients. Design. Randomized, open-label, parallel-group trial.
  
  
  METHODS
  A medical center and one of its teaching hospitals in Taiwan.
  
  
  METHODS
  Twenty-two de novo kidney transplant recipients.
  
  
  METHODS
  Patients received cyclosporine microemulsion or tacrolimus capsules twice/day in combination with once-daily sirolimus solution and corticosteroids. Sirolimus was administered 6 hours after the morning dose of cyclosporine or tacrolimus. After receiving a 6-mg loading dose of sirolimus, participants received sirolimus 2 mg/day for at least 7 days. Neither the cyclosporine nor the tacrolimus dosage was adjusted for at least 3 days before and during blood sampling for pharmacokinetic profiling.
  
  
  RESULTS
  One patient dropped out because of trimethoprim-sulfamethoxazole-related hepatotoxicity. We observed no differences between the two patient groups in terms of their demographic data, renal and liver function, or dosage of sirolimus during the study. During multiple-dose administration, the area under the whole-blood concentration-time curve and the peak and trough concentrations of sirolimus in the cyclosporine group were, respectively, 1.46 (95% confidence interval [CI] 1.21-1.71), 1.42 (95% CI 1.08-1.76), and 1.42 (95% CI 1.09-1.76) times higher than those of the tacrolimus group, even though sirolimus was administered 6 hours after the other agents.
  
  
  CONCLUSIONS
  Sirolimus pharmacokinetics may change significantly when calcineurin inhibitors are switched, even with staggered administration, which may not completely prevent a drug interaction between cyclosporine and sirolimus solution.
authors.affiliation: College of Medicine, National Taiwan University; Department of Pharmacy, National Taiwan University Hospital, Taipei. flwu@ha.mc.ntu.edu.tw
authors.forename: Fe-Lin Lin
authors.initials: FL
authors.lastname: Wu
authors.forename: Meng-Kun
authors.initials: MK
authors.lastname: Tsai
authors.forename: Russel Rhei-Long
authors.initials: RR
authors.lastname: Chen
authors.forename: Shao-Wen
authors.initials: SW
authors.lastname: Sun
authors.forename: Jin-Ding
authors.initials: JD
authors.lastname: Huang
authors.forename: Rey-Heng
authors.initials: RH
authors.lastname: Hu
authors.forename: Kuo-Hsin
authors.initials: KH
authors.lastname: Chen
authors.forename: Po-Huang
authors.initials: PH
authors.lastname: Lee
mesh_terms: D000328:Adult; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D020123:Sirolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D065095:Calcineurin Inhibitors; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D020123:Sirolimus; D016559:Tacrolimus