Fixed- or Controlled-Dose Mycophenolate Mofetil with Standard- or Reduced-Dose Calcineurin Inhibitors: The Opticept Trial

Gaston, Robert S.; Kaplan, Bruce; Shah, Tariq; Cibrik, Diane M.; Shaw, Les; Angelis, Michael; Mulgaonkar, Shamkant; Meier-Kriesche, Herwig Ulf; Patel, Dharmesh; Bloom, Roy D.

doi:10.1111/j.1600-6143.2009.02668.x

Cited by 165 publications

(148 citation statements)

References 32 publications

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“…In the control arm 20 studies utilized tacrolimus as the maintenance CNI (n ϭ 3289) and 35 used ciclosporin (n ϭ 7568), with one study 53 incorporating both calcineurin inhibitors. The individual immunosuppressant regimens and study lengths for all of the randomized controlled trials are summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Sharif

Shabir

Chand

et al. 2011

Journal of the American Society of Nephrology

127

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Calcineurin-inhibitor-sparing strategies in kidney transplantation may spare patients the adverse effects of these drugs, but the efficacy of these strategies is unknown. Here, we conduct a meta-analysis to assess outcomes associated with reducing calcineurin inhibitor exposure from the time of transplantation. We search Medline, Embase, and Cochrane Register of Controlled Trials for randomized controlled trials published between 1966 and 2010 that compared de novo calcineurin-inhibitor-sparing regimens to calcineurin-inhibitor-based regimens. In this analysis, we include 56 studies comprising data from 11337 renal transplant recipients. Use of the contemporary agents belatacept or tofacitinib, in combination with mycophenolate, decreased the odds of overall graft failure (OR 0.61; 95% CI 0.39 -0.96; P ϭ 0.03). Similarly, minimization of calcineurin inhibitors in combination with various induction and adjunctive agents reduces the odds of graft failure (OR 0.73; 95% CI 0.58 -0.92; P ϭ 0.009). Conversely, the use of inhibitors of mammalian target of rapamycin (mTOR), in combination with mycophenolate, increases the odds of graft failure (OR 1.43; 95% CI 1.08 -1.90; P ϭ 0.01). Calcineurin-inhibitor-sparing strategies are associated with less delayed graft function (OR 0.89; 95% CI 0.80 -0.98; P ϭ 0.02), improved graft function, and less new-onset diabetes. The more contemporary protocols did not seem to increase rates of acute rejection. In conclusion, this meta-analysis suggests that reducing exposure to calcineurin inhibitors immediately after kidney transplantation may improve clinical outcomes.

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Section: Resultsmentioning

confidence: 99%

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Sharif

Shabir

Chand

et al. 2011

Journal of the American Society of Nephrology

127

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“…On the contrary, with the same initial dose of MMF, only a minority of Caucasian patients had MPA levels above minimum therapeutic level (Mourad et al, 2001;van Gelder et al, 2008;Gaston et al, 2009;de Winter et al, 2011). In studies with Asian patients, it was found that after an initial MMF dose of 750 mg twice-a-day, instead of 1000 mg, comparable efficacy with a lower incidence of adverse events (leukopenia, gastrointestinal symptoms, and cytomegalovirus infection) was achieved (Jirasiritham et al, 2004;Jiao et al, 2007).…”

Section: Discussionmentioning

confidence: 96%

Study on the association of UGT1A9 gene c.98T>C polymorphism and mycophenolic acid plasma levels in renal transplant patients

Ruschel

Schmitt

Silva³

et al. 2017

Genet. Mol. Res.

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ABSTRACT. Mycophenolate mofetil (MMF) is a prodrug active only after its hydrolysis to mycophenolic acid (MPA). The UGT1A9 enzyme is of special interest since it is the main enzyme involved in the glucuronidation of MPA. Single nucleotide polymorphisms (SNPs) in the UGT1A9 gene may be responsible for individual differences in the pharmacokinetics of MMF. Expression levels and the activity of UGT1A9 may depend on the presence of some SNPs located in the gene promoter region (-2152C>T and -275T>A), as well as changes in the coding region (c.98T>C). The objective of this study was to evaluate the effect of allelic variants of the UGT1A9 c.98T>C polymorphism (rs72551330; g. 87289T>C) on MMF metabolism in 2 L.R. Ruschel et al.Genetics and Molecular Research 16 (2): gmr16029598 renal transplant patients. MPA and MPA 7-O glucuronide (MPAG) levels were determined on plasma samples of kidney transplant patients (N = 39) by high-performance liquid chromatography using ultraviolet detection. DNA was isolated from leukocytes and stored at -20°C. The presence of SNPs was investigated using polymerase chain reaction, followed by amplicon sequencing. The analysis of the UGT1A9 c.98T>C polymorphism revealed that all study patients presented the TT genotype. Diverse MPA and MPAG plasma concentrations were detected, including therapeutic, subtherapeutic, and toxic levels. A standardized molecular method permitted identification of UGT1A9 c.98T>C polymorphism genotypes in the examined renal transplant patients. All individuals of the study group presented the same genotype (c.98TT) for that polymorphism. Thereby, no association between the c.98T>C polymorphism and MPA and MPAG plasma levels could be evaluated, despite different levels of these compounds being observed.

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“…The Opticept Trial compared a concentration-controlled dose of MMF with a fixed-dose regimen. 34 Patients received either the concentration-controlled MMF and reduced-level CNI, concentration-controlled MMF and standardlevel CNI, or fixed-dose MMF and standard-level CNI. There were no major differences at 2 years between the fixed-dose and the concentrationcontrolled MMF groups, indicating the potential utility of concentration-controlled MMF in CNIsparing regimens.…”

Section: Calcineurinmentioning

confidence: 99%

Untitled

Camilleri

Bridson

Halawa³

2016

Exp Clin Transplant

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The introduction of the calcineurin inhibitors cyclosporine and tacrolimus in the immuno suppressive regimens for kidney transplant has been associated with substantial reductions in the incidence of acute rejection, with a subsequent improvement in 1-year graft survival. However, this has not directly correlated with improvements in long-term allograft survival. Immunosuppressive medications are associated with toxicities related directly to immunosuppressive effects, and these are similar among different agents. In addition, there are other toxicities that are unique for each drug. Immunosuppressive minimization strategies have attempted to address both of these toxicities. Calcineurin inhibitors have been associated with chronic nephrotoxicity, and various calcineurin inhibitor-sparing strategies have been used to address this issue with the aim of improving long-term outcomes. However, there has been a paradigm shift over the past 10 to 15 years, with the appreciation that calcineurin inhibitor nephrotoxicity is not the major cause of late graft failure. Studies have now shown that chronic immune injury mediated by donorspecific antibodies may account for most late graft losses. Although some patients do benefit from calcineurin inhibitor-sparing approaches, others may have late allograft loss from chronic and subacute immune-mediated injury. Unfortunately, the vast majority of calcineurin inhibitor-sparing studies have short-term follow-up and have not explored the change in the donor-specific antibody profile. One of the biggest challenges that we face is being able to distinguish among patients who will benefit from this strategy and those who will not. In this study, we review the various strategies used to limit or avoid the use of calcineurin inhibitors and address the benefits and pitfalls associated in pursuing such strategies.

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Fixed- or Controlled-Dose Mycophenolate Mofetil with Standard- or Reduced-Dose Calcineurin Inhibitors: The Opticept Trial

Cited by 165 publications

References 32 publications

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Meta-Analysis of Calcineurin-Inhibitor-Sparing Regimens in Kidney Transplantation

Study on the association of UGT1A9 gene c.98T>C polymorphism and mycophenolic acid plasma levels in renal transplant patients

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