Efficacy of Achieving Early Target Trough Levels of Tacrolimus Using CYP3A5 Guided Dosing Versus Weight-based Dosing in a Multi-ethnic Population of Kidney Transplant Recipients in Singapore

Overview

The investigators hypothesise that the adaptation of CYP3A5 genotype-based Tacrolimus (FK) dosing will lead to earlier FK target achievement and consequently, better clinical outcome after kidney transplantation (RTx). This study aims to shed light on the possible impact of CYP3A genotype-based FK dosing on FK target achievement and clinical outcome after RTx in a multi-ethnic population where current evidence is lacking. This data would be helpful to the physicians so that by knowing the genotype of the patient before undergoing transplantation, practitioners would be able to decide on the starting dose of FK so as to avoid low trough levels and risk of acute rejection or high trough levels and risk of nephrotoxicity.

Tacrolimus (FK) remains the cornerstone of maintenance immunosuppressants after renal transplantation. However, it is characterised by narrow therapeutic index and large inter-individual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations. Among several factors investigated for their possible influence on tacrolimus pharmacokinetics, polymorphisms in genes coding for biotransformation enzymes (cytochrome P450 (CYP) isoenzymes 3A4 and 3A5) have received much attention. Exposure to FK correlates with the cytochrome P450 (CYP) 3A4 and CYP3A5 which are polymorphically expressed. This is in part explained by the presence of single-nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes. To date, renal transplant (RTx) recipients receive standard weight-based dosing of FK and therapeutic drug monitoring is employed for subsequent dose adjustment to ensure target FK concentration is attained. However, the current weight-based dosing strategies to guide the initial FK dosing have been poorly predictive of the actual FK dose required to attain therapeutic FK level. With the increased possibility of sub-therapeutic FK level during the early phase post renal transplantation, it puts them at a higher risk of developing acute rejection. There has been increasing evidence to suggest the implementation of pre-transplantation genotyping to guide the initial FK dose to achieve target FK concentrations as quickly as possible. On the contrary, there are a few studies that report contradictory results of genotype-guided FK dosing as being useful in attainment of target therapeutic levels. Given the differences in CYP3A5 genotype prevalence among races and the controversy in clinical benefits of such a pro-active dosage strategy, the impact of CYP3A5 genotype-guided dosing on clinical outcome remains to be answered, especially in the local multi-ethnic population. This pro-active approach may also sound promising for the local multi-ethnic population where majority of the renal transplant population are CYP3A5 expressers who may require a higher initial dose of FK based on genotyping profile.