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

S Tremblay, V Nigro, J Weinberg, E S Woodle, R R Alloway, S Tremblay, V Nigro, J Weinberg, E S Woodle, R R Alloway

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 , Tmax 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, Cmax was ~17% lower for LCPT than for IR-Tac or ER-Tac; Cmin was ~6% lower for LCPT compared with IR-Tac and 3% higher compared with ER-Tac.

Trial registration: ClinicalTrials.gov NCT02339246.

Keywords: calcineurin inhibitor: tacrolimus; clinical research/practice; clinical trial; immunosuppressant; kidney transplantation/nephrology; pharmacokinetics/pharmacodynamics.

© 2016 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.

Figures

Figure 1
Figure 1
Study design. ER‐Tac, extended‐release tacrolimus; IR‐Tac, immediate‐release tacrolimus; LCPT, once‐daily, MeltDose tacrolimus; PK, pharmacokinetic profiling.
Figure 2
Figure 2
Patient attrition. ER‐Tac, extended‐release tacrolimus; IR‐Tac, immediate‐release tacrolimus; LCPT, once‐daily, MeltDose tacrolimus; PK, pharmacokinetics.
Figure 3
Figure 3
(A) Observed mean whole blood concentrations of tacrolimus based on conversion factors of 1:1:0.80 for IR‐Tac:ER‐Tac:LCPT (upper panel) versus (B) exposure (AUC)‐normalized mean whole blood concentrations of tacrolimus based on conversion factors of 1:1.08:0.70 (lower panel). AUC, area under the curve, ER‐Tac, extended‐release tacrolimus; IR‐Tac, immediate‐release tacrolimus; LCPT, once‐daily, MeltDose tacrolimus; SE, standard error of the mean; TDD, total daily dose.
Figure 4
Figure 4
Group mean daily tacrolimus trough level (ng/mL) determined by the dried blood samples in each period. ER‐Tac, extended‐release tacrolimus; IR‐Tac, immediate‐release tacrolimus; LCPT, once‐daily, MeltDose tacrolimus; SE, standard error of the mean.

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