Tacrolimus - Pharmacokinetic Considerations for Clinicians

Schütte‐Nütgen, Katharina; Thölking, Gerold; Suwelack, Barbara; Reuter, Stefan

doi:10.2174/1389200219666180101104159

Cited by 78 publications

(80 citation statements)

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“…2 Second, in contrast to European studies, Bartlett et al's study included 40% African Americans; ethnicity has a known impact. 6,7 Third, the low rejection rate (e.g., in contrast to Egeland et al), might have masked differences as already stated by the authors. Different induction therapies and missing protocol biopsies, frequently detecting rejection in stable grafts, might be responsible.…”

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confidence: 78%

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Alternative Viewpoint on Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

Thölking¹,

Reuter

2019

Pharmacotherapy

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confidence: 78%

“…2,4 Lower troughs might mitigate tacrolimus adverse effects. 7,9 Fifth, the authors speculate that NRM have a higher exposure to tacrolimus over time, leading to increased toxicity, which is not supported by data. In fact, others showed comparable area under the receiver operating characteristic curve between RM and NRM.…”

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confidence: 90%

Alternative Viewpoint on Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

Thölking¹,

Reuter

2019

Pharmacotherapy

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“…for example, changes in gastrointestinal mobility, albumin, hematocrit, and steroid dosing, to allow valid prediction of the Tac metabolism type before one months after RTx [8,10].…”

Section: Transplant Internationalmentioning

confidence: 99%

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confidence: 99%

Early postoperative calculation of the tacrolimus concentration‐to‐dose ratio does not predict outcomes after kidney transplantation

et al. 2020

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There is an emerging interest in the tacrolimus metabolism rate as it is linked to outcomes after transplantation [1][2][3][4][5][6][7]. We and others propose the concentration-to-dose (C/D) ratio as a simple surrogate for the individual tacrolimus (Tac) metabolism rate [5,8,9]. Recently, Jouve et al. [3] showed in a large retrospective singlecenter study that the C/D ratio was in contrast to the CYP3A5 genotype strongly associated with outcomes after renal transplantation (RTx). They used a C/D ratio cutoff of 1.05 µg/l 9 1/mg, which we used to guide risk stratification of RTx patients, as a low C/D ratio (fast Tac metabolism) is associated with, for example, an increased calcineurin inhibitor nephrotoxicity rate, a lower estimated glomerular filtration rate (eGFR), and five-year patient and overall graft survival [5,9].Initially, we proposed a classification of patient's Tac metabolism rate based on the C/D ratio expressed as the Tac trough level concentration normalized by the dose (mean C/D ratios at one, three, and six months after RTx) [5]. Notably, even a single C/D ratio calculated in stable patients three months after RTx predicted outcomes, as it is relatively stable over time after the third postoperative months [3,9].Since the negative effect of fast Tac metabolism becomes apparent within a month after RTx and the C/ D ratio is a simple but valuable tool to identify patients who might profit from modification of the immunosuppressive regime, we and others asked whether it can be reliable calculated within the first days after RTx to identify high-risk patients very early [5]?To this end, we retrospectively analyzed the data of 882 patients who received a donor kidney at the University Hospital of M€ unster between January 2007 and December 2017. The C/D ratio was calculated for each of the first ten postoperative days in cases of available Tac trough and dosage data and used to categorize patients. C/D ratio cutoff values were calculated for each day based on the ROC curve analysis and the Youden index maximum. We found a C/D ratio of 0.87 on the third day after RTx to allow the best prediction (compared with all other postoperative days) of the 3month Tac metabolism type (AUC = 0.741; P < 0.001). However, using this cutoff, the outcomes of slow and fast metabolizers were comparable showing the absent discriminative power of early postoperative C/D ratios after RTx (Fig. 1). Nevertheless, we would like to emphasize that these results need to be validated in a different data set to avoid biased results that might be too sensitive to the random noise in the given dataset.Additionally, we performed the analogous analyses by using the calculated best predictive cut-point of day 7 post-transplantation (0.88) as a comparatively more conceptualizable time point and calculated the corresponding estimated survival probabilities at one, three, and six months post-transplantation ( Figure S1). Although we found a significant impact on patient survival when this cut-point at 7 days was applied, this finding was...

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“…Tacrolimus (FK506) has become the rst-line immunosuppressant drug used after LT [11][12][13]. We determined the therapeutic e cacy of FK506 in an outbred rat LT model.…”

Section: Introductionmentioning

confidence: 99%

Induction of liver transplant immune tolerance in an outbred rat strain model using tacrolimus Subtitle: Therapeutic effect of tacrolimus in rat orthotopic liver transplantation models

Park

Joo

et al. 2020

Preprint

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Background: Orthotopic liver transplantation is the only option for patients with end-stage liver disease and hepatocellular carcinoma. Acute rejection occurs in 25–50% of all recipients after liver transplantation. Thus, post-transplant immunosuppressive therapy is important to prevent graft failure. Tacrolimus (FK506) is a main immunosuppressive drug used after liver transplantation. Methods: FK506 and postoperative therapy were administered subcutaneously once or twice daily to transplanted rats. Histopathological and immunohistochemical analyses were conducted for all groups. The regulation of inflammatory cytokine signaling in the spleen was analyzed by flow cytometry. Results: FK506 attenuated allograft rejection and increased survival in rat orthotopic liver transplantation models. The FK506-treated group had reduced serum levels of AST, ALT, and ALP. Furthermore, FK506 decreased the expression of inflammatory cytokines and the activation of pathogenic Th1 and Th17 cells in the liver. Conclusions: These results indicate that the FK506 has potential as a therapeutic drug following liver transplantation.

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Tacrolimus - Pharmacokinetic Considerations for Clinicians

Cited by 78 publications

References 0 publications

Alternative Viewpoint on Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

Alternative Viewpoint on Tacrolimus Concentration‐to‐Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes

Early postoperative calculation of the tacrolimus concentration‐to‐dose ratio does not predict outcomes after kidney transplantation

Induction of liver transplant immune tolerance in an outbred rat strain model using tacrolimus Subtitle: Therapeutic effect of tacrolimus in rat orthotopic liver transplantation models

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