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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
Author(s) -
Tremblay S.,
Nigro V.,
Weinberg J.,
Woodle E. S.,
Alloway R. R.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.13935
Subject(s) - cmin , cmax , tacrolimus , medicine , pharmacokinetics , crossover study , urology , pharmacology , transplantation , pathology , placebo , alternative medicine
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 (T max ) to peak concentration (C max ) were found for LCPT versus IR ‐Tac or ER ‐Tac. ER ‐Tac showed no differences versus IR ‐Tac in exposure, C max , T max or 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, C max was ~17% lower for LCPT than for IR‐Tac or ER‐Tac; C min was ~6% lower for LCPT compared with IR ‐Tac and 3% higher compared with ER ‐Tac.