A Comparison of Short-Term Exposure of Once-Daily Extended Release Tacrolimus and Twice-Daily Cyclosporine on Renal Function in Healthy Volunteers

作者：Zaltzman Jeffrey S^*

来源：Transplantation, 2010, 90(11): 1185-1191.

DOI：10.1097/TP.0b013e3181fa4e77

• Renal physiology
• Nephrotoxicity
• Tacrolimus

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 (C(max)) of CsA. The pharmacokinetic (PK) profile of the once-daily formulation of tacrolimus extended release (Tac ER) includes an equivalent AUC(PK 0-24) (hr) and a lower C(max) 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 C(2) of 700 to 1400 ng/mL, and Tac ER was targeted to C(0) 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(0) Tac and CsA were 6.4 +/- 1.16 and 201 +/- 57 ng/mL, respectively. At C(max), the change in ERPF was +30 +/- 127 vs. -70 +/- 96 mL/min/1.73 m(2) 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 m(2) (P=0.027) and 604 +/- 98 vs. 543 +/- 79 mL/1.73 m(2) (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.

• 出版日期2010-12-15