Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations

Abstract

Introduction: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. Areas covered: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. Expert opinion: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a~40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.ARTICLE HISTORY

Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose

“…Especially, CYP3A4*22 is interesting because it is associated with a lower Tac dosage after renal transplantation. 21 …”

Pharmacokinetic considerations related to therapeutic drug monitoring of tacrolimus in kidney transplant patients

“…Individuals are considered expressers of CYP3A5 if they carry at least one CYP3A5*1 allele, whereas individuals homozygous for the CYP3A5*3 allele are classified as CYP3A5 non-expressers. In addition to CYP3A5*3, the CYP3A5*6 and CYP3A5*7 variant alleles can also lead to nonfunctional CYP3A5 protein [90]. There are also ethnic distribution differences of CYP3A5 variant alleles with expressers (carriers of the CYP3A5*1 variant allele) being more frequently found among non-Caucasian populations.…”

Relationship Between Tacrolimus Dosage and Renal Function, Acute Rejection and Early Infections, Single Center Experience

“…Actualmente, hay estudios de genómica y etnicidad que evidencian cada vez más que una dosificación de tacrolimus basada en el genotipo puede mejorar los resultados clínicos. Actualmente, se ha propuesto algoritmos de dosificación que incorporan genética con datos demográficos y clínicos para permitir una dosificación de tacrolimus más precisa 18,19 . Durante el primer mes después de efectuar el trasplante renal, es común encontrar dos causas principales de infección: 1) infección derivada del donador hacia el receptor, y 2) complicaciones infecciosas relacionadas con la cirugía4.…”