CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients

Ferenc Fekete,Katalin Monostory,Annamária Minus,Balázs Sax,Béla Merkely,Katalin Mangó,Máté Déri,Zsófia Szakál-Tóth,Evelyn Incze

doi:10.1038/s41598-021-00942-y

Abstract

High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients’ CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A5*3/*3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A5*1. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A5*1 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.

Highlights

High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes
We have previously demonstrated a strong correlation between CYP3A4 mRNA expression in leukocytes and hepatic CYP3A4 activities[33]
No association was found between various CYP3A4 genotype groups and CYP3A4 expression probably due to the low frequencies of the polymorphic CYP3A4 alleles (CYP3A4*1B: 4.09%; CYP3A4*22: 3.02%) in the heart transplant recipients and/or to non-genetic factors that masked the effect of genotype on CYP3A4 expression (Supplementary Figure S1)

Summary

Introduction

High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. Due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. The contribution of patients’ CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. Monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period. One of the causes, associated with these conditions is recipients’ variability in immunosuppressant pharmacokinetics that contributes to post-transplant outcome. Any factor that can modulate the blood concentrations of immunosuppressants, of tacrolimus influences the outcome of t ransplantation[8,14,15]

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