Identification of Antibiotic Administration as a Potentially Novel Factor Associated With Tacrolimus Trough Variability in Kidney Transplant Recipients: A Preliminary Study

Zheng, YuanPu; Masand, Anjali; Wagner, Michael; Kapur, Sandip; Dadhania, Darshana; Lubetzky, Michelle; Lee, John Richard

doi:10.1097/txd.0000000000000930

Cited by 13 publications

(5 citation statements)

References 18 publications

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“…Several enhanced dosing models have demonstrated improvements in IPV and suggest computer‐assisted dosing, capable of accounting for higher levels of clinical complexity, is another area to target for intervention 75–77 . Further, the understanding of additional sources of tacrolimus variability continues to grow with recent evidence supporting a role for the microbiome and inflammation 78,79 …”

Section: Discussionmentioning

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: Discussionmentioning

confidence: 99%

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

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“…In a retrospective cohort study of 260 kidney transplant recipients, our group recently identified that antibiotic administration is associated with tacrolimus trough variability, thus indirectly supporting a potential role of the gut microbiota on tacrolimus trough variability. 6 …”

mentioning

confidence: 99%

Blood Profiles of Gut Bacterial Tacrolimus Metabolite in Kidney Transplant Recipients

Guo

Lee

Edusei

et al. 2020

Transplantation Direct

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“…While clinical reports have described important variations in TAC blood levels after ATB [ 22 , 23 ], TAC high intra-individual variability has been identified as a risk factor for the graft outcome [ 4 , 11 ]. Importantly, the above-mentioned TAC PK fluctuations observed under antibiotherapy could not be attributed to direct drug-drug interactions (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…Additional lines of evidence support our hypothesis of the existence and the likely importance of an interaction between immunosuppressive therapy and the gut microbiota. Indeed, case reports described alteration in TAC blood concentrations after diarrhoea episodes [ 20 , 21 ] or even antibiotherapy [ 22 , 23 ]. Moreover, a clinical pilot study showed that TAC dose escalation during the first month after transplantation was correlated with the initial abundance of the bacterium Faecalibacterium prausnitzii [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Gut microbiome modulates tacrolimus pharmacokinetics through the transcriptional regulation of ABCB1

et al. 2023

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Background Following solid organ transplantation, tacrolimus (TAC) is an essential drug in the immunosuppressive strategy. Its use constitutes a challenge due to its narrow therapeutic index and its high inter- and intra-pharmacokinetic (PK) variability. As the contribution of the gut microbiota to drug metabolism is now emerging, it might be explored as one of the factors explaining TAC PK variability. Herein, we explored the consequences of TAC administration on the gut microbiota composition. Reciprocally, we studied the contribution of the gut microbiota to TAC PK, using a combination of in vivo and in vitro models. Results TAC oral administration in mice resulted in compositional alterations of the gut microbiota, namely lower evenness and disturbance in the relative abundance of specific bacterial taxa. Compared to controls, mice with a lower intestinal microbial load due to antibiotics administration exhibit a 33% reduction in TAC whole blood exposure and a lower inter-individual variability. This reduction in TAC levels was strongly correlated with higher expression of the efflux transporter ABCB1 (also known as the p-glycoprotein (P-gp) or the multidrug resistance protein 1 (MDR1)) in the small intestine. Conventionalization of germ-free mice confirmed the ability of the gut microbiota to downregulate ABCB1 expression in a site-specific fashion. The functional inhibition of ABCB1 in vivo by zosuquidar formally established the implication of this efflux transporter in the modulation of TAC PK by the gut microbiota. Furthermore, we showed that polar bacterial metabolites could recapitulate the transcriptional regulation of ABCB1 by the gut microbiota, without affecting its functionality. Finally, whole transcriptome analyses pinpointed, among others, the Constitutive Androstane Receptor (CAR) as a transcription factor likely to mediate the impact of the gut microbiota on ABCB1 transcriptional regulation. Conclusions We highlight for the first time how the modulation of ABCB1 expression by bacterial metabolites results in changes in TAC PK, affecting not only blood levels but also the inter-individual variability. More broadly, considering the high number of drugs with unexplained PK variability transported by ABCB1, our work is of clinical importance and paves the way for incorporating the gut microbiota in prediction algorithms for dosage of such drugs.

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Identification of Antibiotic Administration as a Potentially Novel Factor Associated With Tacrolimus Trough Variability in Kidney Transplant Recipients: A Preliminary Study

Abstract: Supplemental Digital Content is available in the text.

Cited by 13 publications

References 18 publications

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Blood Profiles of Gut Bacterial Tacrolimus Metabolite in Kidney Transplant Recipients

Gut microbiome modulates tacrolimus pharmacokinetics through the transcriptional regulation of ABCB1

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