Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients

Charat Thongprayoon,Tarun Bathini,Swetha R Kanduri,Wisit Cheungpasitporn,Justin R Smith,Karthik Kovvuru,Aleksandra Pivovarova,Panupong Hansrivijit

doi:10.3390/jcm9072193

Abstract

Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug’s efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.

Highlights

Calcineurin inhibitor (CNI)-based immunosuppression is a regularly used therapeutic regimen in solid organ transplantation (SOT), tacrolimus being the front-running CNI [1,2] and mainstay of triple immunosuppressive drug regimens [3]
99% of tacrolimus is excreted via bile
Liver dysfunction or bile secretion defects could result in tacrolimus toxicity

Summary

Introduction

Calcineurin inhibitor (CNI)-based immunosuppression is a regularly used therapeutic regimen in solid organ transplantation (SOT), tacrolimus ( known as FK506) being the front-running CNI [1,2] and mainstay of triple immunosuppressive drug regimens [3]. Tacrolimus undergoes extensive hepatic metabolism, and less than 1% of the unaltered parent drug is eliminated [3]. The therapeutic advantages of tacrolimus outweigh its major disadvantages such as the large inter-patient pharmacokinetic (PK) variability and potential risk of drug interactions with co-administrated medications [27]. Inter-individual PK variability can be affected by the amount of time passed since the transplant, patient demographics (age and race), hepatic and renal function, the hematocrit level, food administration, concomitant medications (corticosteroids, antifungals, calcium channel blockers, etc.), and the genotype for metabolic enzymes [16,31] (Table 2). Corticosteroids induce CYP3A4 and P-gp pathways that may potentially influence tacrolimus metabolism, yet the data are conflicting [35]. By influencing the conversion of uridine diphosphoglucuronosyltransferase to the glucuronide metabolite of mycophenolicacid (MPA), tacrolimus may affect mycophenolicacid (MPA) levels [38]

Results in the

Intra-Individual and Inter-Individual Tacrolimus PK Variability

Fast Tacrolimus Metabolizers at Risk

Conclusions