Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients

Abstract

The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.

Keywords: Pharmacogenetics, Calcineurin inhibitors, Tacrolimus, Liver transplant, Kidney transplant, Single nucleotide polymorphisms, CYP3A4, CYP3A5, ABCB1

Core tip: As researchers continue to evaluate the influence of single nucleotide polymorphisms on tacrolimus dosing and on the response to the drug, the challenge now becomes to assess the potential clinical implications of this research for medical practice. Sufficient data have been accumulated to be certain that the liver donor and kidney recipient CYP3A5 genotype has an important influence on tacrolimus dosing and on the observed blood trough levels of the drug. However, the question remains, should genotyping become a standard of practice in transplantation?