Optimization of tacrolimus in kidney transplantation: New pharmacokinetic perspectives

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation (KT), but its use is complicated by a narrow therapeutic index and high inter- and intra-patient pharmacokinetic variability. There are three available oral formulations of tacrolimus: immediate-release tacrolimus (IR-Tac), extended-release tacrolimus (ER-Tac) and a MeltDose® (LCPT) formulation, the latter favoring a prolonged drug release and increased bioavailability. The time-concentration curves of these formulations are different. Compared with IR-Tac and ER-Tac, LCPT has a relatively flat pharmacokinetic profile with less fluctuation between trough and peak exposures, and a delayed peak concentration. This translates to a more stable delivery of tacrolimus and may alleviate the risk of underexposure and allograft rejection or overexposure and toxicity. The once-daily formulation of both ER-TAC and LCPT may also offer a potential advantage on patient adherence. Fast metabolizers of tacrolimus, the elderly, and human leukocyte antigen-sensitized patients are at risk of poorer outcomes after KT, possibly associated with a different exhibited pharmacokinetics of tacrolimus or different requirements in terms of exposure. Simple, practical strategies are needed to identify patients at risk of suboptimal KT outcomes and those who would benefit from a more proactively personalized approach to tacrolimus treatment. This review aims to increase awareness of the link between the pharmacokinetics of oral tacrolimus formulations and the clinical needs of patients after KT, particularly among those who have clinically significant pharmacokinetic variation of tacrolimus.