Customizing Tacrolimus Dosing in Kidney Transplantation: Focus on Pharmacogenetics

Abstract: Different polymorphisms in genes encoding metabolizing enzymes and drug transporters have been associated with tacrolimus pharmacokinetics. In particular, studies on CYP3A4 and CYP3A5, and their combined cluster have demonstrated their significance in adjusting tacrolimus dosing to minimize under- and overexposure thereby increasing the proportion of patients who achieve tacrolimus therapeutic target. Many factors influence the pharmacokinetics of tacrolimus, contributing to inter-patient variability affecting individual dosing requirements. On the other hand, the growing use of population pharmacokinetic models in solid organ transplantation, including different tacrolimus formulations, has facilitated the integration of pharmacogenetic data and other variables into algorithms to easier implement the personalized dose adjustment in transplant centers. The future of personalized medicine in transplantation lies in implementing these models in clinical practice, with pharmacogenetics as a key factor to account for the high inter-patient variability in tacrolimus exposure. To date, three clinical trials have validated the clinical application of these approaches. The aim of this review is to provide an overview of the current studies regarding the different population pharmacokinetic including pharmacogenetics and those translated to the clinical practice for individualizing tacrolimus dose adjustment in kidney transplantation.