Thirty Years of Tacrolimus in Clinical Practice

Ong, Song; Gaston, Robert S.

doi:10.1097/tp.0000000000003350

Cited by 46 publications

(41 citation statements)

References 156 publications

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“…Tacrolimus remains the primary immunosuppressive agent used in solid organ transplantation as it is highly effective at preventing rejection and graft loss compared with other agents 1 . Due to its narrow therapeutic index and extensive pharmacokinetic variability, individualized and frequent dose adjustments are necessary to minimize therapeutic failures, such as rejection and debilitating adverse effects 2 .…”

Section: Introductionmentioning

confidence: 99%

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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Background Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. Methods A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. Results Forty‐four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV‐directed interventions was limited to small preliminary studies. Conclusions High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV‐directed interventions to improve transplant outcomes.

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Section: Introductionmentioning

confidence: 99%

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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“…Precise dose adjustment of TAC is crucial to avoid graft rejection and toxicities after organ transplantation. 24 The DDI between VRC and TAC is inevitable and highly variable in solid organ transplantation, which is a challenge for TAC dose modification. To the best of our knowledge, this is the first study to assess the magnitude of DDI between VRC and TAC in HT patients during the early stage of transplantation.…”

Section: Discussionmentioning

confidence: 99%

Predictors of tacrolimus dose optimization when drug-drug interaction associated with voriconazole in heart transplant recipients

Huang

Zhou

Zhang

et al. 2022

Preprint

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Aims: Voriconazole is the mainstay for the treatment for invasive fungal infections in heart transplant patients and significantly increase tacrolimus exposure because of drug-drug interaction (DDI). However, the magnitude of this DDI is highly variable and hard to predicted. The purpose of this study was to present the characteristics of DDI between tacrolimus and voriconazole, and further identify the predictors of tacrolimus dose modification. Methods: We retrospectively enrolled 69 heart transplant recipients without using voriconazole as the control and 68 patients received voriconazole treatment in voriconazole group. CYP3A4*1G, CYP3A5*3 and CYP2C19*2 or *3 were genotyped by Sanger sequencing. The requirement of tacrolimus dose for therapeutic concentrations and tacrolimus dose-corrected trough concentration (C0/D) before and after VRC administration were evaluated. Results: The DDI between tacrolimus and voriconazole was in a large inter-individual variability with more than ten-fold changes in tacrolimus dose (range 1.28–13.00) and C0/D (range 1.43–13.75). Besides, the fold changes of tacrolimus dose were associated with CYP2C19 genotype, which was significantly lower in CYP2C19 extensive metabolizers than that in CYP2C19 intermediate metabolizers or poor metabolizers (4.06±1.85 vs 5.49±2.47, p=0.0031). While no significant difference was found in both CYP3A4 and CYP3A5 genotypes. Moreover, CYP2C19 genotype and hematocrit were independent predicting factors for tacrolimus dose modification after voriconazole co-therapy. Conclusions: This study provided a potential basis for comprehensive factors to adjust tacrolimus dosage when co-administrated with voriconazole in individual patients. CYP2C19 genotype and hematocrit should be considered in tailoring tacrolimus dose.

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“…While these have led to reasonably safe steroid-free regimens [10][11][12] , CNIs are still the cornerstone of immunosuppression in modern solid organ transplantation. Early graft survival improved greatly after the introduction of cyclosporine (CsA) in the early 1980s 13 , and tacrolimus (TAC) has been the CNI of choice since the 1990s 14 . Despite the bene ts of CNIs in the early post-transplant period, they have dose-dependent side effects, including post-transplant diabetes mellitus (PTDM), hypertension, hypercholesterolemia, and nephrotoxicity, leading to progressive decline in renal graft function [15][16][17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

Calculated cardiovascular risk after conversion from calcineurin inhibitor to belatacept in kidney transplant recipients: A randomized controlled trial

Bredewold

Chan

Svensson

et al. 2022

Preprint

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In renal transplant recipients (RTRs), a belatacept-based immunosuppressive regimen is associated with beneficial effects on cardiovascular (CV) risk factors compared with calcineurin inhibitor (CNI)-based regimens. The aim of this randomized, multi-national trial was to compare calculated CV risk between belatacept and CNI (predominantly tacrolimus) treatments using a valdidated model developed for RTRs. From 9 transplant centers, RTRs from 3 to 60 months post-transplantation were recruited to either continue treatment with a CNI-based regimen or switch to belatacept. We compared the change in estimated 7-year risk of major adverse cardiovascular events (MACE) and all-cause mortality after 12 months of treatment. In the 105 RTRs randomized, we found no differences between the treatment groups in predicted risk for MACE or mortality. Diastolic blood pressure was lower after belatacept treatment compared with CNI. The mean changes in traditional CV risk factors, including renal transplant function, were otherwise similar in both treatment groups. The belatacept group had four acute rejection episodes; two were severe rejections, of which one led to graft loss. In conclusion, we found no effects on calculated CV risk by switching to belatacept treatment.

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Thirty Years of Tacrolimus in Clinical Practice

Cited by 46 publications

References 156 publications

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Predictors of tacrolimus dose optimization when drug-drug interaction associated with voriconazole in heart transplant recipients

Calculated cardiovascular risk after conversion from calcineurin inhibitor to belatacept in kidney transplant recipients: A randomized controlled trial

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