title: A randomized cross-over comparison of short-term exposure of once-daily extended release tacrolimus and twice-daily tacrolimus on renal function in healthy volunteers.
abstract: Calcineurin inhibitor nephrotoxicity remains an issue for transplant recipients. The pharmacokinetic profile (PK) of the once-daily tacrolimus extended release (Tac-ER) includes equivalent exposure [AUC(0-24 h) ] but lower Cmax versus twice-daily tacrolimus immediate release (Tac-IR). We hypothesized that the unique PK profiles would result in pharmacodynamic differences in renal function. Nineteen healthy male subjects were allocated to once-daily Tac-ER and twice-daily Tac-IR in a prospective, randomized, two period, cross-over study. Tacrolimus was titrated to achieve trough levels of 8-12 ng/ml. Twenty four hours ERPF and GFR estimated by para-aminohippurate and sinistrin clearance were performed at baseline and at the end of each 10-day dosing period. Mean Tac C0 was 11.0 ± 2.2 and 11.3 ± 1.8 ng/ml for Tac-ER and Tac-IR, respectively. The mean Effective 24 h renal plasma flow (ERPF) was significantly higher with Tac-ER compared with Tac-IR (658 ± 127 vs. 610 ± 93 ml/min/1.73 m(2) , P = 0.046). There was a trend to a greater mean GFR over 24 h for Tac-ER at 114.5 ± 13.6 ml/min/1.73 m(2) compared with 108.9 ± 9.7 ml/min/1.73 m(2) for Tac-IR, P = 0.116. Under controlled physiological conditions, ERPF was significantly improved with Tac-ER compared with Tac-IR, likely owing to the differing PKs of these tacrolimus preparations (ClinicalTrials.gov Identifier: NCT01681134).
authors.affiliation: Renal Transplant Program, Department of Medicine, Li Ka Shing Institute St. Michael's University of Toronto, Toronto, ON, Canada.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Zaltzman
authors.forename: Vesta
authors.initials: V
authors.lastname: Lai
authors.forename: Miklos Z
authors.initials: MZ
authors.lastname: Schulz
authors.forename: Kyung-Hee
authors.initials: KH
authors.lastname: Moon
authors.forename: David Z
authors.initials: DZ
authors.lastname: Cherney
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000293:Adolescent; D000328:Adult; D000450:Aldosterone / Q000097:blood; D065095:Calcineurin Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D064368:Healthy Volunteers; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000097:blood; D011446:Prospective Studies; D012079:Renal Circulation / Q000187:drug effects*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000494:pharmacology / Q000633:toxicity; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D009569:Nitric Oxide; D000450:Aldosterone; D015121:6-Ketoprostaglandin F1 alpha; D016559:Tacrolimus
keywords: nephrotoxicity; renal physiology; tacrolimus