title: Reduced C0 concentrations and increased dose requirements in renal allograft recipients converted to the novel once-daily tacrolimus formulation.
abstract: BACKGROUND
  Recently, a once-daily prolonged release formulation of tacrolimus (TacOD) has been approved for the prevention of renal allograft rejection. Studies reported equivalent area under the concentration-time curve0-24 and predose trough (C0) concentrations when compared with the standard twice-daily tacrolimus (Tac) formulation. Hence, the package insert advices a 1:1 mg conversion. Here, we report our independent experience with conversion to TacOD according to the manufacturer's instructions.
  
  
  METHODS
  Retrospective single-center study evaluating the evolution of C0 concentrations and dose requirements after conversion to TacOD in 284 renal allograft recipients. Potential clinical, biochemical, and genetic determinants of changes in C0 concentrations and dose requirements after conversion were explored in univariate and multivariate analyses.
  
  
  RESULTS
  After conversion, C0 concentrations decreased significantly (-1.36+/-2.51 microg/L or -12.66%+/-24.36%, P<0.0001). In 38.3% of patients, this decrease exceeded 20%. TacOD dose was increased in 52.5% of patients. Average dose requirements increased to 0.71+/-1.78 mg/day or 14.68%+/-28.87% (P<0.0001). In 28.0% of patients, dose requirements increased more than 20%. Dose changes were more profound in patients converted within 1 year after transplantation, and in this subgroup (n=78), higher creatinine and lower hemoglobin levels were associated with a larger increase in dose requirements in multivariate analysis (r=0.35, P<0.0001). Despite dose adjustments, average C0 concentrations remained 9.09%+/-28.85% lower after conversion (P<0.0001).
  
  
  CONCLUSIONS
  Conversion from standard twice-daily tacrolimus formulation to TacOD on a 1:1 mg basis results in reduced Tac C0 concentrations and increased dose requirements. Thus, conversion is not as straightforward as suggested by the manufacturer, and converted patients should be monitored strictly until stable C0 concentrations are achieved.
authors.affiliation: Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hylke
authors.initials: H
authors.lastname: de Jonge
authors.forename: Dirk R
authors.initials: DR
authors.lastname: Kuypers
authors.forename: Kristin
authors.initials: K
authors.lastname: Verbeke
authors.forename: Yves
authors.initials: Y
authors.lastname: Vanrenterghem
mesh_terms: D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus