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.
This study evaluates the pharmacokinetic profile of three tacrolimus formulations and shows significant differences, highlighting the higher per mg exposure and a lower peak and delayed peak of extended-release tacrolimus tablets when compared to the two other capsule formulations.