Comparative clinical trial of the variability factors of the exposure indices used for the drug monitoring of two tacrolimus formulations in kidney transplant recipients

[Display omitted] Several studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics. 45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC–MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0–24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC0–24h and the AUC-to-trough concentration ratios. The Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p