Canadian multicentre trial of tacrolimus/azathioprine/steroids versus tacrolimus/mycophenolate mofetil/steroids versus neoral/mycophenolate mofetil/steroids in renal transplantation

Busque, S.; Shoker, Ahmed; Landsberg, David; McAlister, Vivian C.; Halloran, Philip F.; Shapiro, Jamie; Peets, J.; Schulz, Miklos

doi:10.1016/s0041-1345(00)02471-4

Cited by 18 publications

(13 citation statements)

References 2 publications

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“…Intention to treat analysis was confirmed for 12 trials,16 19 21 25 – 27 29 – 31 37 40 41 not done for eight trials,15 18 22 24 28 32 34 36 and unclear for 10 trials. Completeness of follow-up was neither reported nor deducible for 10 trials12 – 14 17 23 28 31 32 36 38; it ranged between 77% and 100% for the remainder.…”

Section: Resultsmentioning

confidence: 98%

See 1 more Smart Citation

Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data

Webster

Woodroffe

Taylor

et al. 2005

BMJ

515

301

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Objective To compare the positive and negative effects of tacrolimus and ciclosporin as initial treatment for renal transplant recipients. Design Systematic review. Data sources and study selection Reports of comparative randomised trials of tacrolimus and ciclosporin identified by searches of Medline, Embase, the Cochrane Register of Controlled Trials, the Cochrane Renal Group Specialist Register, and conference proceedings. Data extraction and synthesis Two reviewers assessed trials for eligibility and quality and extracted data independently. Data were synthesised (random effects model) and results expressed as relative risk (RR), with values < 1 favouring tacrolimus. Subgroup analysis and meta-regression were used to examine potential effect modification by differences in trial design and immunosuppressive co-interventions. Results 123 reports from 30 trials (4102 patients) were included. At six months, graft loss was significantly reduced in tacrolimus treated recipients (RR = 0.56, 95% confidence interval 0.36 to 0.86), and this effect persisted up to three years. The relative reduction in graft loss with tacrolimus diminished with higher concentrations of tacrolimus (P = 0.04) but did not vary with ciclosporin formulation (P = 0.97) or ciclosporin concentration (P = 0.38). At one year, tacrolimus treated patients had less acute rejection (RR = 0.69, 0.60 to 0.79) and less steroid resistant rejection (RR = 0.49, 0.37 to 0.64) but more diabetes mellitus requiring insulin (RR = 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia, and vomiting. The relative excess of diabetes increased with higher concentrations of tacrolimus (P = 0.003). Ciclosporin treated recipients had significantly more constipation and cosmetic side effects. No differences were seen in infection or malignancy. Conclusions Treating 100 recipients with tacrolimus instead of ciclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes. Optimal drug choice may vary between patients.

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Section: Resultsmentioning

confidence: 98%

“…Three trials varied the antiproliferative agent across three trial arms, investigating combinations of tacrolimus and ciclosporin with mycophenolate or azathioprine 14 21 38. Azathioprine was used in both tacrolimus and ciclosporin arms in 16 trials and mycophenolate in eight trials.…”

Section: Resultsmentioning

confidence: 99%

Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data

Webster

Woodroffe

Taylor

et al. 2005

BMJ

515

301

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“…Combining mycophenolate mofetil with tacrolimus instead of cyclosporin A in renal transplantation not only results in high clinical efficacy 1 , 2 (acute rejection rates ranging from 8.7%–22.9%) but also in a 100% higher dose‐corrected exposure to mycophenolic acid (MPA), measured by the dose interval area under the plasma concentration versus time curve (AUC 0–12 h ) and the plasma MPA predose concentration (C 0 ) 3 , 4 . Indirect experimental 5 – 7 and clinical 8 – 10 evidence indicates that the most important reason for this differential effect of calcineurin inhibitors on MPA exposure is the interruption of enterohepatic recirculation (EHC) of the 7‐OH‐glucuronide of MPA (MPAG) and MPA by cyclosporin A, which can be responsible for up to 37% of the total measured dose interval AUC 11 .…”

mentioning

confidence: 99%

Long‐Term Changes in Mycophenolic Acid Exposure in Combination with Tacrolimus and Corticosteroids Are Dose Dependent and Not Reflected by Trough Plasma Concentration: A Prospective Study in 100 De Novo Renal Allograft Recipients

Kuypers

Claes

Evenepoel

et al. 2003

The Journal of Clinical Pharma

105

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Tacrolimus and cyclosporine A have different effects on exposure to concomitantly administered mycophenolate mofetil (MMF), measured as the mycophenolic acid (MPA) dose interval area under the plasma concentration versus time curve (AUC0-12 h) or the plasma MPA predose concentration (C0). This has led to recommendations in using a 50% lower dose of MMF in combination with tacrolimus compared to cyclosporin A. At present, no long-term data are available regarding the pharmacokinetics (PK) of different dosages of MMF in combination with tacrolimus and the clinical variables that influence the dose-exposure relationship of MPA. A prospective 12-month pharmacokinetic study was performed in 100 de novo renal transplant recipients treated with two different MMF dosages (1 g/day vs. 2 g/day) in combination with tacrolimus and corticosteroids. MPA AUC data were collected 7 days, 6 weeks, and 3 and 12 months posttransplantation, and model-independent PK parameters were calculated. Clinical variables that could possibly influence MPA PK were evaluated. The MPA AUC0-12 h significantly increased toward 6 weeks (p < 0.05) but only in the 2-g MMF dosing group. The MPA AUC0-12 h in the 1-g MMF group reached its nadir at 3 months, while in the 2-g MMF group, it remained elevated until 3 months, returning to baseline values by 12 months. This differential evolution in exposure was not only inadequately reflected by the corresponding MPA C0 concentrations, but the MPA C0 concentrations also were not significantly different between the two dosing groups at early postgrafting (day 7) and at 12 months. Using multiple stepwise regression analysis, C0 (r = 0.51, p < 0.0001) and end-of-dose interval MPA plasma concentration (C12: r2 = 0.61, p < 0.0001) were found to poorly predict MPA AUC0-12 h, while MPA plasma concentrations at 4 hours (C4: r2 = 0.85, p < 0.0001) and 6 hours postdosing (C6: r2 = 0.83, p < 0.0001) were superior but hampered by a large prediction bias and imprecision. An abbreviated 2-hour AUC measurement (r2 = 0.78), using three sampling points (C0, C40 [MPA plasma concentration 40 min postdosing], C2), provided the best compromise between a monitoring tool that is theoretically ideal and practically feasible. MPA pharmacokinetics were not influenced by recipient age, gender, and body weight or by serum albumin concentrations, allograft function, or corticosteroid or tacrolimus dose. Mild hepatic dysfunction early after grafting did result in significantly reduced MPA exposure (MPA AUC0-12 h, p = 0.01 and C0, p = 0.03). In this study, it was demonstrated for the first time that the dynamics of long-term MPA pharmacokinetics in combination with tacrolimus differ according to the daily MMF dose and that this effect is not adequately reflected by MPA trough concentrations. Using the latter as a routine measure for therapeutic drug monitoring might mislead clinicians into drawing wrong conclusions in terms of relating questions of efficacy or toxicity to MPA exposure.

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“…Of these, six and seven used the Sandimmun and Neoral formulations of ciclosporin, respectively. [90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] Only one RCT was identified that was conducted exclusively in children. 107 G All the RCTs were open label and few provided details of the methods of randomisation or allocation concealment.…”

Section: Discussionmentioning

confidence: 99%

“…Seven RCTs comparing tacrolimus to Neoral in adults and one RCT in children met the inclusion criteria of this review. [90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108] The details of these trials are presented in Appendices 10 and 20.…”

Section: Quantity Of Evidencementioning

confidence: 99%

Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study

Woodroffe¹,

Yao²,

Meads³

et al. 2005

Health Technol Assess

166

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The newer immunosuppressant drugs (basiliximab, daclizumab, tacrolimus and MMF) consistently reduced the incidence of short-term (1-year) acute rejection compared with conventional immunosuppressive therapy. The independent use of basiliximab, daclizumab, tacrolimus and MMF was associated with a similar absolute reduction in 1-year acute rejection rate (approximately 15%). However, the effects of these drugs did not appear to be additive (e.g. benefit of tacrolimus with adjuvant MMF was 5% reduction in acute rejection rate compared with 15% reduction with adjuvant AZA). Thus, the addition of one of these drugs to a baseline immunosuppressant regimen was likely to affect adversely the incremental cost-effectiveness of the addition of another. The trials did not assess how the improvement in short-term outcomes (e.g. acute rejection rate or measures of graft function), together with the side-effect profile associated with each drug, translated into changes in patient-related quality of life. Moreover, given the relatively short duration of trials, the impact of the newer immunosuppressants on long-term graft loss and patient survival remains uncertain. The absence of both long-term outcome and quality of life from trial data makes assessment of the clinical and cost-effectiveness on the newer immunosuppressants contingent on modelling based on extrapolations from short-term trial outcomes. The choice of the most appropriate short-term outcome (e.g. acute rejection rate or measures of graft function) for such modelling remains a matter of clinical and scientific debate. The decision to use acute rejection in the meta-model in this report was based on the findings of a systematic review of the literature of predictors of long-term graft outcome. Only a very small proportion of the RCTs identified in this review assessed patient-focused outcomes such as quality of life. Since immunosuppressive drugs have both clinical benefits and specific side-effects, the balance of these harms and benefits could best be quantified through future trials using quality of life measures. The design of future trials should be considered with a view to the impact of drugs on particular renal transplant groups, particularly higher risk individuals and children. Finally, there is a need for improved reporting of methodological details of future trials, such as the method of randomisation and allocation concealment. A number of issues exist around registry data, for example the use of multiple drug regimens and the need to assess the long-term outcomes. An option is the use of observational registry data including, if possible, prospective data on all consecutive UK renal transplant patients. Data capture for each patient should include immunosuppressant regimens, clinical and patient-related outcomes and patient demographics.

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Canadian multicentre trial of tacrolimus/azathioprine/steroids versus tacrolimus/mycophenolate mofetil/steroids versus neoral/mycophenolate mofetil/steroids in renal transplantation

Cited by 18 publications

References 2 publications

Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data

Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data

Long‐Term Changes in Mycophenolic Acid Exposure in Combination with Tacrolimus and Corticosteroids Are Dose Dependent and Not Reflected by Trough Plasma Concentration: A Prospective Study in 100 De Novo Renal Allograft Recipients

Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study

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