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Journal ArticleDOI

Therapeutic Monitoring of Calcineurin Inhibitors for the Nephrologist

01 Mar 2007-Clinical Journal of The American Society of Nephrology (Clin J Am Soc Nephrol)-Vol. 2, Iss: 2, pp 374-384
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.

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Citations
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Journal ArticleDOI
TL;DR: The importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations is emphasized, and single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy.
Abstract: In 2007, a consortium of European experts on tacrolimus (TAC) met to discuss the most recent advances in the drug/dose optimization of TAC taking into account specific clinical situations and the analytical methods currently available and drew some recommendations and guidelines to help clinicians with the practical use of the drug. Pharmacokinetic, pharmacodynamic, and more recently pharmacogenetic approaches aid physicians to individualize long-term therapies as TAC demonstrates a high degree of both between- and within-individual variability, which may result in an increased risk of therapeutic failure if all patients are administered a uniform dose. TAC has undoubtedly benefited from therapeutic drug monitoring, but interpretation of the blood concentration is confounded by the relative differences between the assays. Single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy. Therapeutic trough TAC concentration ranges have changed since the initial introduction of the drug, while still maintaining adequate immunosuppression and avoiding drug-related adverse effects. Pharmacodynamic markers have also been considered advantageous to the clinician, which may better reflect efficacy and safety, taking into account the between-individual variability rather than whole blood concentrations. The choice of method, differences between methods, and potential pitfalls of the method should all be considered when determining TAC concentrations. The recommendations of this consensus meeting regarding the analytical methods include the following: encourage the development and promote the use of analytical methods displaying a lower limit of quantification (1 ng/mL), perform careful validation when implementing a new analytical assay, participate in external proficiency testing programs, promote the use of certified material as calibrators in high-performance liquid chromatography with mass spectrometric detection methods, and take account of the assay and intermethod bias when comparing clinical trial outcomes. It is also important to consider that TAC concentrations may also be influenced by other factors such as specific pharmacokinetic characteristics associated with the population, drug interactions, pharmacogenetics, adverse events that may alter TAC concentrations, and any change in the oral formulation that may result in pharmacokinetic changes. This meeting emphasized the importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations whether it is other single time points or area under the concentration-time curve Bayesian estimation using limited sampling strategies and to select, standardize, and validate routine biomarkers of TAC pharmacodynamics.

427 citations

Journal ArticleDOI
TL;DR: Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity.
Abstract: The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes — in particular, CYP3A4 and CYP3A5 — and are transported out of cells via P-glycoprotein (ABCB1) Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 —392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1 128503) and ABCB1 2677G>T/A (rs2032582) The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacodynamics of ciclosporin and tacrolimus in solid-organ transplant recipients Literature searches were performed and all relevant primary research articles were critiqued and summarized There is no evidence that the CYP3A4 —392A>G SNP has an effect on the pharmacodynamics of either ciclosporin or tacrolimus; however, studies have been limited For patients prescribed ciclosporin, the CYP3A5 6986A>G SNP may influence long-term survival, possibly because of a different metabolite pattern over time This SNP has no clear association with acute rejection during ciclosporin therapy Despite a strong association between the CYP3A5 6986A>G SNP and tacrolimus pharmacokinetics, there is no consistent evidence of organ rejection as a result of genotype-related under-immunosuppression This is likely to be explained by the practice of performing tacrolimus dose adjustments in the early phase after transplantation The effect of the CYP3A5 6986A>G SNP on ciclosporin-and tacrolimus-related nephrotoxicity and development of hypertension is unclear Similarly, the ABCB1 SNPs exert no clear influence on either ciclosporin or tacrolimus pharmacodynamics, with studies showing conflicting results in regard to the main parameters of acute rejection and nephrotoxicity In kidney transplant patients, consideration of the donor kidney genotype rather than the recipient genotype may be more important when assessing development of nephrotoxicity Studies with low patient numbers may account for many inconsistent results to date The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect Further haplotype analyses are likely to be useful, particularly ones that consider both donor and recipient genotype The effects of polymorphisms associated with the pregnane X receptor, organic anion transporting polypeptides, calcineurin inhibitor target sites and immune response pathways need to be further investigated A large standardized clinical trial is now required to evaluate the relationship between the pharmacokinetics and pharmacodynamics of CYP3A5-mediated tacrolimus metabolism, particularly in regard to the outcomes of acute rejection and nephrotoxicity It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy

320 citations

Journal ArticleDOI
TL;DR: In this article, the authors provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year.
Abstract: Short-term patient and graft outcomes continue to improve after kidney and liver transplantation, with 1-year survival rates over 80%; however, improving longer-term outcomes remains a challenge. Improving the function of grafts and health of recipients would not only enhance quality and length of life, but would also reduce the need for retransplantation, and thus increase the number of organs available for transplant. The clinical transplant community needs to identify and manage those patient modifiable factors, to decrease the risk of graft failure, and improve longer-term outcomes.COMMIT was formed in 2015 and is composed of 20 leading kidney and liver transplant specialists from 9 countries across Europe. The group's remit is to provide expert guidance for the long-term management of kidney and liver transplant patients, with the aim of improving outcomes by minimizing modifiable risks associated with poor graft and patient survival posttransplant.The objective of this supplement is to provide specific, practical recommendations, through the discussion of current evidence and best practice, for the management of modifiable risks in those kidney and liver transplant patients who have survived the first postoperative year. In addition, the provision of a checklist increases the clinical utility and accessibility of these recommendations, by offering a systematic and efficient way to implement screening and monitoring of modifiable risks in the clinical setting.

200 citations

Journal ArticleDOI
TL;DR: Tacrolimus (FK506) and cyclosporine (cyclosporin A, CsA) are cornerstone immunosuppressive agents administered to solid organ transplant recipients to prevent and treat allograft rejection.
Abstract: Tacrolimus (FK506) and cyclosporine (cyclosporin A, CsA) are cornerstone immunosuppressive agents administered to solid organ transplant recipients to prevent and treat allograft rejection. The discovery of cyclosporine in the 1970s, and its entry into the collection of immunosuppressants in the early 1980s, was a major breakthrough in medicine. Cyclosporine was the most successful antirejection drug to date, and it radically improved the chance of survival for transplant recipients. In 1994, the Food and Drug Administration (FDA) approved tacrolimus, an effective alternative to cyclosporine [1]. Since then, tacrolimus and cyclosporine have become the principal immunosuppressive drugs for solid organ transplantation. The United States Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients showed that in 2011, 86% of the 16 055 patients who received a kidney transplant were prescribed tacrolimus upon discharge, and 2.4% were prescribed cyclosporine. One year after transplant, 84 and 4% of patients received tacrolimus and cyclosporine therapy, respectively [2]. Global differences exist in the usage of tacrolimus and cyclosporine: 2008 figures from the Australia and New Zealand Dialysis and Transplant Registry show that 61% of the 391 Australian patients who received a deceased kidney donor graft were prescribed tacrolimus, and 35% were prescribed cyclosporine. At 1-year post-transplant, these numbers changed to 55 and 33% for tacrolimus and cyclosporine, respectively [3]. Both drugs are also prescribed for liver, intestinal, lung, and heart transplant recipients [2], and can be used to manage severe autoimmune conditions, such as atopic dermatitis [4,5] and rheumatoid arthritis [6,7]. Tacrolimus and cyclosporine differ in their chemical structure: cyclosporine is a cyclic endecapeptide [8], whereas tacrolimus is a macrocyclic lactone [9]. However, they act in a similar manner. Both are calcineurin inhibitors; their main mechanism of action involves inhibition of this important phosphatase [1]. Tacrolimus exhibits similar effects to cyclosporine, but at concentrations 100 times lower [10]. Despite these differences in potency, tacrolimus and cyclosporine both show excellent survival rates for grafts across many comparative studies (summarized in Maes and Vanrenterghem [11]). However, several studies have shown that use of tacrolimus is associated with a lower allograft rejection rate compared with cyclosporine [12-14]. The principal adverse effects associated with tacrolimus and cyclosporine treatment are neurotoxicity, nephrotoxicity, hypertension, hyperglycemia, gastrointestinal disturbances, infections, and malignancy [15]. Although the two drugs have similar side-effect profiles, they may differ in the frequency of effects. For example, tacrolimus is more likely to cause alopecia [16], tremors [17], and new-onset diabetes mellitus [12], whereas cyclosporine is associated with hyperlipidemia [18], hypertrichosis, and gingival hyperplasia [19]. The idea that tacrolimus is less nephrotoxic than cyclosporine remains controversial [20], particularly as most studies of renal injury are based on evaluations in renal transplant patients, making it difficult to discriminate between drug-induced organ damage and other causes of organ dysfunction [21]. A recent study in pancreatic transplant recipients examined baseline kidney biopsies and 5-year post-transplant biopsies, and reported that the chronic nephrotoxic effects of tacrolimus and cyclosporine were similar [20]. Despite the success of both drugs, treatment is complicated by narrow therapeutic indices and large intrapatient and interpatient pharmacokinetic variability [22,23]. Although adequate exposure is essential to prevent rejection, overexposure can lead to toxicities that reduce tolerability and affect long-term allograft and patient survival [24]. Therapeutic drug monitoring (TDM), therefore, is mandatory for both drugs. However, because individual transplant recipients respond differently to similar immunosuppressant concentrations, achieving the recommended therapeutic target range does not guarantee absence of drug toxicity or complete immunosuppressant efficacy. A mechanistic understanding of the underlying factors affecting the pharmacokinetics and pharmacodynamics of calcinuerin inhibitors may prove useful in being able to further personalize these therapies. This review aims to provide a broad overview of recently published literature on the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tacrolimus and cyclosporine in transplant patients, with the goals of clarifying current understanding and identifying areas of future research. In doing so, this review builds on the work of others in this field [1,8,24-27]. A particular emphasis is given to pharmacogenetics, as developments in this area may provide a way to optimize treatment with these drugs, potentially avoiding negative side effects while still maintaining efficacy.

176 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.

144 citations


Cites background from "Therapeutic Monitoring of Calcineur..."

  • ...Routine monitoring of drug levels and concentrationcontrolled dosing is now common practice for cyclosporine, tacrolimus, sirolimus, and everolimus though no prospective randomized trials directly compared concentration-controlled dosing with fixed dosing regimens for these drugs.(1,6,7) Although there is a rationale for TDM for MPA as well, it remains a matter of ongoing debate whether concentrationcontrolled dosing of its prodrug mycophenolate mofetil (MMF) is superior to using a fixed drug dose....

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  • ...Both cyclosporine and tacrolimus fulfill the major criteria that make a drug a suitable candidate for TDM, and therefore, CNI TDM is part of standard clinical practice for many years now.(1,21) Given the good correlation between tacrolimus C0 (predose trough level) and tacrolimus exposure [dose interval area under the concentration–time curve (AUC)] (r(2) = 0....

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References
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Journal ArticleDOI
TL;DR: It is concluded that long-term cyclosporine therapy may lead to irreversible and potentially progressive nephropathy and should be used with restraint and caution until ways are found to mitigate its nephrotoxicity.
Abstract: We evaluated glomerular filtration in 17 recipients of heart transplants who were treated for 12 months or longer with cyclosporine (cyclosporin A). The control group consisted of 15 heart-transplant recipients who were treated with azathioprine and who had also survived for at least 12 months. Despite an equivalent cardiac output, the glomerular filtration rate was depressed (51 +/- 4 vs. 93 +/- 3 ml per minute, P less than 0.005) in transplant recipients treated with cyclosporine. Cyclosporine treatment was also associated with reduced renal plasma flow (320 +/- 21 vs. 480 +/- 30 ml per minute, P less than 0.001). A trend toward restricted transglomerular transport of neutral dextrans (radii, 2.4 to 5.8 nm) in cyclosporine-treated recipients suggested an intrinsic loss of ultrafiltration capacity by glomerular capillaries rather than a hemodynamic basis for the reduced glomerular filtration rate. Histopathologic examination of the kidneys of five cyclosporine-treated patients with glomerular hypofiltration revealed a variable degree of tubulointerstitial injury accompanied by focal glomerular sclerosis. Among the 32 heart-transplant recipients treated for more than 12 months with cyclosporine at our center, end-stage renal failure developed in 2. We conclude that long-term cyclosporine therapy may lead to irreversible and potentially progressive nephropathy. We recommend that cyclosporine be used with restraint and caution until ways are found to mitigate its nephrotoxicity.

1,072 citations

Journal ArticleDOI
TL;DR: Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations.
Abstract: Background. Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. Methods. A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. Results. One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. Conclusions. Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.

1,060 citations

Journal ArticleDOI
TL;DR: 34 patients treated with cyclosporin A received 36 cadaveric organ allografts, 26 kidneys are still supporting life, 3 after more than a year; the pancreases and livers are also functioning.

985 citations

Journal ArticleDOI
TL;DR: Use of sirolimus reduced occurrence and severity of biopsy-confirmed acute rejection episodes with no increase in complications and further studies are needed to establish the optimum doses for the combined regimen.

905 citations

Journal ArticleDOI
TL;DR: A significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.
Abstract: Background. To confirm the results of a number of studies conducted in Europe, the United States, and Japan, this multicenter, randomized trial compared the 12-month efficacy and safety of tacrolimus- and cyclosporine-based immunosuppressive regimens in the prevention of renal allograft rejection. Methods. A total of 448 renal transplant recipients were recruited from 15 centers and assigned to receive triple-drug therapy consisting of tacrolimus (n=303) or cyclosporine (n=145) in conjunction with azathioprine and low-dose corticosteroids. Results. At 12 months after transplantation, tacrolimus therapy was associated with a significant reduction in the frequency of both acute (tacrolimus 25.9% vs. cyclosporine 45.7%; P<0.001 [absolute difference: 19.8%, 95% confidence interval: 10.0-29.6%]) and corticosteroid-resistant rejection (11.3% vs. 21.6%; P=0.001 [absolute difference: 10.3%, 95% confidence interval: 2.5-18.2%]). Actuarial 1-year patient (tacrolimus 93.0% vs. cyclosporine 96.5%; P=0.140) and graft survival rates (82.5% vs. 86.2%; P=0.380) did not differ significantly between the two treatment groups. Overall, the safety profiles of the tacrolimus- and cyclosporine-based regimens were quite comparable. Infections, renal impairment, neurological complications, and gastrointestinal complaints were frequently reported but were mostly reversible in both groups. Higher incidences of elevated serum creatinine, tremor, diarrhea, hyperglycemia, diabetes mellitus, and angina pectoris were reported in the tacrolimus treatment group, whereas acne, arrhythmia, gingival hyperplasia, and hirsutism were more frequent with cyclosporine treatment. Conclusions. The significant reduction in the incidence of episodes of allograft rejection observed with tacrolimus therapy may have important long-term implications given the prognostic influence of rejection on graft survival.

718 citations

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