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Journal ArticleDOI

Pharmacodynamic monitoring of cyclosporine a in renal allograft recipients shows a quantitative relationship between immunosuppression and the occurrence of recurrent infections and malignancies.

27 Nov 2006-Transplantation (Transplantation)-Vol. 82, Iss: 10, pp 1280-1285

TL;DR: Recurrent infectious complications and the degree of suppression of NFAT-regulated genes by CsA in transplanted patients are correlated with the frequency of recurrent infections and malignancies in patients with five or more years of follow-up posttransplantation.

AbstractBACKGROUND: At present it is unclear which dose and consecutive blood levels of cyclosporine A (CsA) are optimal with respect to immunosuppressive efficacy and drug specific side effects at the level of individual patients. Several pharmacodynamic measures of CsA effects have been proposed, but have not become clinical routine yet. Besides the lack of practicability, the biological relevance of these assays has not been determined so far. METHODS: Residual expression of nuclear factor of activated T-cells (NFAT)-regulated genes two hours after drug intake was used as molecular pharmacodynamic marker to assess CsA effects on lymphocytes and correlated with the frequency of recurrent infections and malignancies in patients with five or more years of follow-up posttransplantation. RESULTS: Recurrent infectious complications were observed in 44% and malignancies in 20% of the 133 patients studied. Patients with a strong suppression of NFAT-regulated genes by CsA--as judged by a residual level of transcription of less than 15% after drug intake--develop more frequent infections (53% vs. 29%; P = 0.005) and malignancies (22% vs. 4%; P = 0.002). The lack of correlation between the incidence of these complications and CsA blood concentration might point to the interindividual differences in the sensitivity towards calcineurin inhibition. CONCLUSION: The data presented here reveal a clear relation between the frequency of infectious and malignant complications and the degree of suppression of NFAT-regulated genes by CsA in transplanted patients. Therefore, pharmacodynamic monitoring of CsA efficacy in transplanted patients might be a useful tool to adjust immunosuppressive therapy in individual patients.

Topics: Immunosuppression (51%), Calcineurin (50%)

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Journal ArticleDOI
TL;DR: The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications and discusses the effect of adjunctive immunosuppressive agents on CNI Pharmacokinetic and dosing.
Abstract: The calcineurin inhibitors (CNI) cyclosporine and tacrolimus remain the backbone of immunosuppression for most kidney transplant recipients. Despite many years of experience, protocols that optimize efficacy with minimal toxicity remain a subject of debate. Nevertheless, studies of the pharmacokinetic properties of the CNI, particularly cyclosporine, have led to improved dosing strategies. The purpose of this article is to review the current understanding of CNI pharmacokinetics and its relevance to proper dosing and monitoring of these medications. This article also reviews the trials that have helped to define the optimal dosages and discusses the effect of adjunctive immunosuppressive agents on CNI pharmacokinetics and dosing.

207 citations


Cites background from "Pharmacodynamic monitoring of cyclo..."

  • ...A recent study measured expression of nuclear factor of activated T cells–regulated genes and found a close relationship between the degree of gene suppression and the incidence of infections and malignancies (108)....

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Journal ArticleDOI
TL;DR: It is concluded that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade, and the Expert Committee concludes that Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacolimus therapy and to improve long-term outcomes for treated patients.
Abstract: Ten years ago, a consensus report on the optimization of tacrolimus was published in this journal. In 2017, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicity (IATDMCT) decided to issue an updated consensus report considering the most relevant advances in tacrolimus pharmacokinetics (PK), pharmacogenetics (PG), pharmacodynamics, and immunologic biomarkers, with the aim to provide analytical and drug-exposure recommendations to assist TDM professionals and clinicians to individualize tacrolimus TDM and treatment. The consensus is based on in-depth literature searches regarding each topic that is addressed in this document. Thirty-seven international experts in the field of TDM of tacrolimus as well as its PG and biomarkers contributed to the drafting of sections most relevant for their expertise. Whenever applicable, the quality of evidence and the strength of recommendations were graded according to a published grading guide. After iterated editing, the final version of the complete document was approved by all authors. For each category of solid organ and stem cell transplantation, the current state of PK monitoring is discussed and the specific targets of tacrolimus trough concentrations (predose sample C0) are presented for subgroups of patients along with the grading of these recommendations. In addition, tacrolimus area under the concentration-time curve determination is proposed as the best TDM option early after transplantation, at the time of immunosuppression minimization, for special populations, and specific clinical situations. For indications other than transplantation, the potentially effective tacrolimus concentrations in systemic treatment are discussed without formal grading. The importance of consistency, calibration, proficiency testing, and the requirement for standardization and need for traceability and reference materials is highlighted. The status for alternative approaches for tacrolimus TDM is presented including dried blood spots, volumetric absorptive microsampling, and the development of intracellular measurements of tacrolimus. The association between CYP3A5 genotype and tacrolimus dose requirement is consistent (Grading A I). So far, pharmacodynamic and immunologic biomarkers have not entered routine monitoring, but determination of residual nuclear factor of activated T cells-regulated gene expression supports the identification of renal transplant recipients at risk of rejection, infections, and malignancy (B II). In addition, monitoring intracellular T-cell IFN-g production can help to identify kidney and liver transplant recipients at high risk of acute rejection (B II) and select good candidates for immunosuppression minimization (B II). Although cell-free DNA seems a promising biomarker of acute donor injury and to assess the minimally effective C0 of tacrolimus, multicenter prospective interventional studies are required to better evaluate its clinical utility in solid organ transplantation. Population PK models including CYP3A5 and CYP3A4 genotypes will be considered to guide initial tacrolimus dosing. Future studies should investigate the clinical benefit of time-to-event models to better evaluate biomarkers as predictive of personal response, the risk of rejection, and graft outcome. The Expert Committee concludes that considerable advances in the different fields of tacrolimus monitoring have been achieved during this last decade. Continued efforts should focus on the opportunities to implement in clinical routine the combination of new standardized PK approaches with PG, and valid biomarkers to further personalize tacrolimus therapy and to improve long-term outcomes for treated patients.

158 citations


Journal ArticleDOI
TL;DR: New insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) are highlighted and the possible consequences are discussed.
Abstract: Although therapeutic drug monitoring (TDM) of immunosuppressive drugs has been an integral part of routine clinical practice in solid organ transplantation for many years, ongoing research in the field of immunosuppressive drug metabolism, pharmacokinetics, pharmacogenetics, pharmacodynamics, and clinical TDM keeps yielding new insights that might have future clinical implications. In this review, the authors will highlight some of these new insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) and will discuss the possible consequences. For CNIs, important relevant lessons for TDM can be learned from the results of 2 recently published large CNI minimization trials. Furthermore, because acute rejection and drug-related adverse events do occur despite routine application of CNI TDM, alternative approaches to better predict the dose-concentration-response relationship in the individual patient are being explored. Monitoring of CNI concentrations in lymphocytes and other tissues, determination of CNI metabolites, and CNI pharmacogenetics and pharmacodynamics are in their infancy but have the potential to become useful additions to conventional CNI TDM. Although MPA is usually administered at a fixed dose, there is a rationale for MPA TDM, and this is substantiated by the increasing knowledge of the many nongenetic and genetic factors contributing to the interindividual and intraindividual variability in MPA pharmacokinetics. However, recent, large, randomized clinical trials investigating the clinical utility of MPA TDM have reported conflicting data. Therefore, alternative pharmacokinetic (ie, MPA free fraction and metabolites) and pharmacodynamic approaches to better predict drug efficacy and toxicity are being explored. Finally, for MPA and tacrolimus, novel formulations have become available. For MPA, the differences in pharmacokinetic behavior between the old and the novel formulation will have implications for TDM, whereas for tacrolimus, this probably will not to be the case.

136 citations


Journal ArticleDOI
TL;DR: Cylex ImmuKnow assay monitoring has the potential to identify the patients atrisk of developing infection and those colonized with fungus that are at risk of developing disease.
Abstract: Background. Lung transplants, in particular, have the highest rate of infections among solid organ transplant recipients. However, there is no existing objective measure to predict the development of infections. We report the correlation between Cylex ImmuKnow (ng/mL ATP) values and various infectious syndromes in a large prospective cohort of lung transplant recipients. Methods. We followed up 175 lung transplants that developed 129 infectious episodes. Multiple logistic regression analysis was performed; generalized estimating equations were used to determine the odds ratio for infections. Results. The median ImmuKnow values in cytomegalovirus disease (49.3 ng/mL ATP), viral infection (70 ng/mL ATP), and bacterial pneumonia (92 ng/mL ATP) were significantly different from stable state (174.8 ng/mL ATP). The median ImmuKnow values of fungal disease (85 ng/mL ATP) and tracheobronchitis (123 ng/mL ATP) had a tendency to be lower than stable state (P=0.10), whereas patients with fungal colonization had comparable ImmunKnow values (167 vs. 174.8 ng/mL ATP). Of the patients colonized with fungus who subsequently developed fungal disease within 100 days, the median value of ImmuKnow was significantly lower than in those who did not develop fungal disease (22.5 vs. 183.5 ng/mL ATP; P<0.0001). Generalized estimating equation regression analysis showed ImmuKnow values less than or equal to 100 ng/mL ATP to be an independent predictor of infections (odds ratio 2.81). Conclusions. Cylex ImmuKnow assay monitoring has the potential to identify the patients at risk of developing infection and those colonized with fungus that are at risk of developing disease.

73 citations


Cites result from "Pharmacodynamic monitoring of cyclo..."

  • ...Immunosuppressive drug levels commonly used to determine the net state of immunosuppression has yielded conflicting results (14, 15)....

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Journal ArticleDOI
TL;DR: It is suggested that the measurement of the relative gene expression in CsA-treated patients is a promising tool to monitor the Cs a dosage reduction in long-term renal transplant patients.
Abstract: Background. The impact of long-term immunosuppression in renal transplant recipients with respect to safety and efficacy remains undetermined. Pharmacodynamic monitoring of the relative reduction of T-cell-specific gene expression in renal transplant recipients treated with cyclosporine A (CsA) was applied in this study. Methods. During the study, 20 stable renal transplant recipients with tapered CsA dose and 20 patients with stable CsA dose (matched for age, gender, CsA dose, time after transplantation) were compared for a median period of 18 months (range 6-44). CsA dose was tapered in two stages of 15% each, and the expression of the nuclear factor of activated T cells (NFAT)-regulated genes was determined by reverse-transcription polymerase chain reaction method at CsA trough level and 2 hr after oral uptake. Results. The initial residual gene expression at 2 hr after CsA intake increased from 6.31% (range 1.30-16.6) to 21.3% (range 6.58-31.8) in patients with CsA dosage reduction. In one patient, the residual gene expression increased more than 40% and resulted in a reversible Banff 1A rejection episode. Blood pressure was significantly lower after CsA dosage reduction (P<0.05). In the pair-matched control group NFAT-regulated gene expression was comparable before and after the follow-up period (7.45% [range 0.21-18.3] vs. 5.87% [rangeO.66-13.2]; P=NS). Estimated glomerular filtration rate was significantly worse in the control group (P<0.05). Conclusion. Our observation suggests that the measurement of the relative gene expression in CsA-treated patients is a promising tool to monitor the CsA dosage reduction in long-term renal transplant patients. An increase in residual expression of NFAT-regulated gene expression may result in an acute rejection episode.

67 citations


Cites background or result from "Pharmacodynamic monitoring of cyclo..."

  • ...In a considerable number of patients, however, only 5% residual NFAT activity was detected (17)....

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  • ...When infectious diseases are excluded, the intraindividual variation is below 10% over a period of several months when compared to the preceding result (17)....

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  • ...Moreover, the safe reduction of CsA may result in reduced drug-specific side effects, importantly with respect to infectious complications and posttransplant cancer (17)....

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  • ...In comparison, patients without infection and/or malignancy demonstrated a relative reduction of NFAT-regulated gene expression of 80% or even less (17)....

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References
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Journal ArticleDOI
TL;DR: There has been a substantial increase in short-term and long-term survival of kidney grafts from both living and cadaveric donors since 1988.
Abstract: Background The introduction of cyclosporine has resulted in improvement in the short-term outcome of renal transplantation, but its effect on the long-term survival of kidney transplants is not known. Methods We analyzed the influence of demographic characteristics (age, sex, and race), transplant-related variables (living or cadaveric donor, panel-reactive antibody titer, extent of HLA matching, and cold-ischemia time), and post-transplantation variables (presence or absence of acute rejection, delayed graft function, and therapy with mycophenolate mofetil and tacrolimus) on graft survival for all 93,934 renal transplantations performed in the United States between 1988 and 1996. A regression analysis adjusted for these variables was used to estimate the risk of graft failure within the first year and more than one year after transplantation. Results From 1988 to 1996, the one-year survival rate for grafts from living donors increased from 88.8 to 93.9 percent, and the rate for cadaveric grafts increased...

1,671 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...With the introduction of calcineurin inhibitors, long-term allograft survival has significantly improved (1), primarily by reduction of acute rejection episodes....

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Journal ArticleDOI
25 Jun 1992-Nature
TL;DR: It is reported here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription.
Abstract: THE immunosuppressive drugs cyclosporin A (CsA) and FKS06 both interfere with a Ca2+-sensitive T-cell signal transduction pathway1–4thereby preventing the activation of specific transcription factors (such as NF-AT and NF-IL2A)1,5–7involved in lymphokine gene expression. CsA and FK506 seem to act by interaction with their cognate intracellular receptors8–10, cyclophilin and FKBP, respectively (see ref. 11 for review). The Ca2+/calmodulin-regulated phosphatase calcineurin is a major target of drug-isomerase complexes in vitro12We have therefore tested the hypothesis that this interaction is responsible for the in vivo effects of CsA/FK506. We report here that overexpression of calcineurin in Jurkat cells renders them more resistant to the effects of CsA and FK506 and augments both NFAT- and NFIL2A-dependent transcription. These results identify calcineurin as a key enzyme in the T-cell signal transduction cascade and provide biological evidence to support the notion that the interaction of drug-isomerase complexes with calcineurin underlies the molecular basis of CsA/FK506-mediated immunosuppression.

1,612 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...Calcineurin is a key component of T-cell activation and serves as the target of the CsA cyclophilin complex (16)....

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Journal ArticleDOI
TL;DR: It is found that halving of trough blood cyclosporin concentrations significantly changes graft function or graft survival, and the design of long-term maintenance protocols for transplant recipients based on powerful immunosuppressant combinations should take these potential risks into account.
Abstract: The introduction of cyclosporin into maintenance therapy for kidney-transplant recipients has played an important part in the improvement of graft survival reported worldwide [1]. Cyclosporin is potentially toxic to various tissues including kidney, liver, endocrine pancreas, and nervous system, and its use is associated with hypertension [2]. Nevertheless, the capacity of cyclosporin treatment to increase graft survival has been recognised for a long time. Optimum doses and trough blood concentrations of cyclosporin have been empirically evolved so as to cause the least kidney toxicity. However, cyclosporin has other potential side-effects related to its immunosuppressant properties, including the occurrence of infections and tumours. The magnitude of these effects may also vary with dose and consequent trough blood concentrations. Thus, there is potential for improvement in dose schedules. In terms of reducing long-term complications of immunosuppression, such as cancers [3], kidney recipients are unlike other organ-graft recipients because long-term dialysis is a viable alternative.

652 citations


Journal ArticleDOI
TL;DR: CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation and strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.
Abstract: BACKGROUND The role and burden of cyclosporine (CsA) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented. METHODS The authors evaluated 888 prospective protocol kidney biopsy specimens from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity. RESULTS The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis, predicted by CsA dose and functional CsA nephrotoxicity. Striped fibrosis was associated with early initiation of CsA and the need for posttransplant dialysis (both P < 0.05). The 10-year cumulative Kaplan-Meier prevalence of arteriolar hyalinosis, striped fibrosis, and tubular microcalcification was 100%, 88.0%, and 79.2% of kidneys, respectively. Beyond 1 year, 53.9% had two or more lesions of CsA nephrotoxicity. Structural CsA nephrotoxicity occurred in two phases, with different clinical and histologic characteristics. The acute phase occurred with a median onset 6 months after transplantation, was usually reversible, and was associated with functional CsA nephrotoxicity (P < 0.05), high CsA levels (P < 0.05), and mild arteriolar hyalinosis (P < 0.001). The chronic phase of CsA nephrotoxicity persisted over several biopsies, occurred at a median onset of 3 years, and was associated with lower CsA doses and trough levels (both P < 0.05). It was largely irreversible and accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis (both P < 0.001). A threshold CsA dose of 5 mg/kg/day predicted worsening of arteriolar hyalinosis on sequential histology. CONCLUSIONS Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy. CsA is unsuitable as a universal, long-term immunosuppressive agent for kidney transplantation. Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed.

458 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...However, rational means to balance both the benefits and side effects of CsA treatment are not sufficiently established yet (2, 3)....

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Journal ArticleDOI
TL;DR: CsA induces partial CN inhibition that varies directly with the blood and tissue levels, and may be greater in some tissues due to higher drug accumulation, relevant to nephrotoxicity.
Abstract: Background Cyclosporine (CsA) acts by inhibiting the phosphatase calcineurin (CN), but the time course and extent of inhibition in vivo are unknown. We examined the effect of single oral CsA doses on CN activity in humans and mice in vivo. Methods In humans, blood CsA levels were determined and CN activity was measured in whole blood and in blood leukocytes of patients up to 12 hr after CsA dosing (just before the second dose). Samples were collected from patients receiving a first single dose (2.5 mg/kg), and up to 14 days later after repeated dosing. In mice, after CsA dosing (12.5-200 mg/kg) by oral gavage, CsA levels in blood and tissue (spleen, kidney) were determined and CN activity was measured in spleen and kidney. Results In humans, peak CsA levels of 800-2285 microg/L at 1-2 hr produced 70-96% CN inhibition. Inhibition correlated closely with the rise and fall of CsA levels with no observable lag at the times sampled. Repeated doses showed similar CN inhibition to first dose, with no significant adaptation. In mice, CsA peaked at 1 hr in blood, spleen, and kidney, with higher concentrations in spleen and kidney than in blood. CN inhibition closely followed CsA concentrations/doses, and was greater in kidney than spleen. Conclusion Thus CsA induces partial CN inhibition that varies directly with the blood and tissue levels, and may be greater in some tissues due to higher drug accumulation. The high CsA concentrations and CN inhibition in kidney may be relevant to nephrotoxicity.

308 citations


"Pharmacodynamic monitoring of cyclo..." refers background in this paper

  • ...(11) demonstrated that the immunosuppressive action for CsA, when measured as inhibition of calcineurin activity in lymphocytes, is inversely correlated with CsA blood levels....

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  • ...In humans, peak CsA blood levels at one to two hours after oral CsA uptake resulted in a 70 to 96% inhibition of calcineurin, which was rapidly reversed when CsA blood levels came down to the trough levels (10, 11)....

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