Monitoring Intra-cellular Tacrolimus Concentrations in Solid Organ Transplantation: Use of Peripheral Blood Mononuclear Cells and Graft Biopsy Tissue.

Benedetta C Sallustio

doi:10.3389/fphar.2021.733285

Abstract

Tacrolimus is an essential immunosuppressant for the prevention of rejection in solid organ transplantation. Its low therapeutic index and high pharmacokinetic variability necessitates therapeutic drug monitoring (TDM) to individualise dose. However, rejection and toxicity still occur in transplant recipients with blood tacrolimus trough concentrations (C0) within the target ranges. Peripheral blood mononuclear cells (PBMC) have been investigated as surrogates for tacrolimus’s site of action (lymphocytes) and measuring allograft tacrolimus concentrations has also been explored for predicting rejection or nephrotoxicity. There are relatively weak correlations between blood and PBMC or graft tacrolimus concentrations. Haematocrit is the only consistent significant (albeit weak) determinant of tacrolimus distribution between blood and PBMC in both liver and renal transplant recipients. In contrast, the role of ABCB1 pharmacogenetics is contradictory. With respect to distribution into allograft tissue, studies report no, or poor, correlations between blood and graft tacrolimus concentrations. Two studies observed no effect of donor ABCB1 or CYP3A5 pharmacogenetics on the relationship between blood and renal graft tacrolimus concentrations and only one group has reported an association between donor ABCB1 polymorphisms and hepatic graft tacrolimus concentrations. Several studies describe significant correlations between in vivo PBMC tacrolimus concentrations and ex vivo T-cell activation or calcineurin activity. Older studies provide evidence of a strong predictive value of PBMC C0 and allograft tacrolimus C0 (but not blood C0) with respect to rejection in liver transplant recipients administered tacrolimus with/without a steroid. However, these results have not been independently replicated in liver or other transplants using current triple maintenance immunosuppression. Only one study has reported a possible association between renal graft tacrolimus concentrations and acute tacrolimus nephrotoxicity. Thus, well-designed and powered prospective clinical studies are still required to determine whether measuring tacrolimus PBMC or graft concentrations offers a significant benefit compared to current TDM.

Highlights

The first calcineurin inhibitor (CNI), ciclosporin, revolutionised solid organ transplantation in the early 1980s providing, for the first time, immunosuppression that selectively targeted T-cell mediated rejection
Despite relatively high therapeutic ranges, a continuing significant incidence of rejection and nephrotoxicity spurred the development of induction therapy and the establishment of triple maintenance immunosuppression consisting primarily of tacrolimus co-administered with a corticosteroid and mycophenolic acid (Wallemacq et al, 2009)
C0Blood were measured with an immunoassay associated with significant metabolite cross-reactivity (Wallemacq et al, 2009). This was followed by another study in liver transplant recipients (Table 1A) again reporting significantly lower liver tacrolimus concentrations in patients with moderate/ severe histological rejection compared to those with no/mild rejection, and a significant relationship between liver tacrolimus concentrations and Banff scores (Capron et al, 2012)

Summary

INTRODUCTION

The first calcineurin inhibitor (CNI), ciclosporin, revolutionised solid organ transplantation in the early 1980s providing, for the first time, immunosuppression that selectively targeted T-cell mediated rejection. Zahir et al provided the first evidence for a possible clinical benefit of measuring PBMC tacrolimus concentrations in a study of 40 adult liver transplant recipients They reported that a lower proportion of total blood tacrolimus was associated with the leucocyte fraction in patients with rejection compared to those without (Zahir et al, 2004a; Zahir et al, 2004b). Two other clinical studies that measured PBMC tacrolimus concentrations in liver transplants have included clinical outcome data These more recent studies recruited patients receiving triple maintenance immunosuppression with tacrolimus, mycophenolic acid and a corticosteroid (Lemaitre et al, 2015; Rayar et al, 2018). In 10 de novo liver transplant recipients studied on days 1 and 7 following commencement of tacrolimus therapy Lemaitre et al (2015) reported that, over a 12-h dosing interval, inhibition of PBMC CNA on day 1 mirrored tacrolimus concentrations in both blood and PBMC, with an average maximum inhibition of 38% occurring slightly after attainment of maximum tacrolimus concentrations in blood (CmaxBlood) and PBMC (CmaxPBMC)

Ex-vivo Pharmacodynamic Assessments

Kidney Transplants

Liver Transplants

Findings

CONCLUSION