title: A comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily cyclosporine on renal function in healthy volunteers.
abstract: BACKGROUND
  Calcineurin inhibitor nephrotoxicity remains an issue for recipients of solid organ transplants. After cyclosporine A (CsA) microemulsion administration, effective renal plasma flow (ERPF) and glomerular filtration rate(GFR) are decreased coincident with the maximal concentration (Cmax) of CsA. The pharmacokinetic (PK) profile of the once-daily formulation of tacrolimus extended release (Tac ER) includes an equivalent AUCPK 0-24 hr and a lower Cmax versus twice-daily Tac immediate release.
  
  
  METHODS
  Eighteen healthy subjects were allocated once-daily Tac ER and twice-daily CsA in a prospective, randomized,open-label, two-period, two-sequence single crossover study. CsA was targeted to C2 of 700 to 1400 ng/mL, and Tac ER was targeted to C0 of 5 to 10 ng/mL. Pharmacodynamic (PD) assessments were conducted preexposure, and PD and PK were assessed during a 6-hr postdose period after 10-day exposure.
  
  
  RESULTS
  The achieved mean C(o) Tac and CsA were 6.4 +/- 1.16 and 201 +/- 57 ng/mL, respectively. At Cmax, the change in ERPF was +30 +/- 127 vs. -70 +/- 96 mL/min/1.73 m2 relative to baseline for Tac ER and CsA (P=0.0085). The ERPF and GFR AUC (PD 0-6) hr were 3645 +/- 887 vs. 3210 +/- 582 mL/1.73 m2 (P=0.027) and 604 +/- 98 vs. 543+/- 79 mL/1.73 m2(P=0.023) for Tac ER versus CsA, respectively. Both systolic and diastolic blood pressures were significantly greater with exposure to CsA compared with Tac ER.
  
  
  CONCLUSIONS
  Acute reductions in ERPF and GFR are attenuated with Tac ER compared with CsA and may correlate with the differing PK profiles of these calcineurin inhibitors.
authors.affiliation: Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada. jeffrey.zaltzman@utoronto.ca
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Zaltzman
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D065095:Calcineurin Inhibitors; D002170:Canada; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D011446:Prospective Studies; D017596:Renal Plasma Flow, Effective / Q000187:drug effects; D016559:Tacrolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus