title: A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study.
abstract: This two-sequence, three-period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice-daily immediate-release tacrolimus capsules [IR-Tac]; once-daily extended-release tacrolimus capsules [ER-Tac]; novel once-daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR-Tac:ER-Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0-8.0) mg for IR-Tac and ER-Tac and 4.8 (3.3-6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (Tmax) to peak concentration (Cmax) were found for LCPT versus IR-Tac or ER-Tac. ER-Tac showed no differences versus IR-Tac in exposure, Cmax, Tmaxor fluctuation. The observed exposure of IR-Tac was used to normalize exposure for LCPT and ER-Tac, resulting in the following recommended total daily dose conversion rates: IR-Tac:ER-Tac, +8%; IR-Tac:LCPT, -30%; ER-Tac:LCPT, -36%. After exposure normalization, Cmaxwas ~17% lower for LCPT than for IR-Tac or ER-Tac; Cminwas ~6% lower for LCPT compared with IR-Tac and 3% higher compared with ER-Tac.
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: S
authors.initials: S
authors.lastname: Tremblay
authors.affiliation: Veloxis Pharmaceuticals, Inc., Edison, NJ.
authors.forename: V
authors.initials: V
authors.lastname: Nigro
authors.affiliation: Veloxis Pharmaceuticals, Inc., Edison, NJ.
authors.forename: J
authors.initials: J
authors.lastname: Weinberg
authors.affiliation: Department of Surgery, Division of Transplantation, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: E S
authors.initials: ES
authors.lastname: Woodle
authors.affiliation: Department of Internal Medicine, Division of Nephrology and Hypertension, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: R R
authors.initials: RR
authors.lastname: Alloway
mesh_terms: D000328:Adult; D018592:Cross-Over Studies; D004339:Drug Compounding; D005260:Female; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: calcineurin inhibitor: tacrolimus; clinical research/practice; clinical trial; immunosuppressant; kidney transplantation/nephrology; pharmacokinetics/pharmacodynamics