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British Journal of Clinical Pharmacology Apr 2019Various mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in...
Systematic external evaluation of published population pharmacokinetic models of mycophenolate mofetil in adult kidney transplant recipients co-administered with tacrolimus.
AIMS
Various mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors.
METHODS
The external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated.
RESULTS
Fifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models.
CONCLUSIONS
The published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF.
Topics: Adult; Aged; Area Under Curve; Datasets as Topic; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Models, Biological; Mycophenolic Acid; Tacrolimus; Young Adult
PubMed: 30597603
DOI: 10.1111/bcp.13850 -
BioMed Research International 2018Graves' ophthalmopathy (GO) is a complicated autoimmune disease. Various therapies have been used to manage GO; however the optimum therapy is not clear. Glucocorticoids... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Graves' ophthalmopathy (GO) is a complicated autoimmune disease. Various therapies have been used to manage GO; however the optimum therapy is not clear. Glucocorticoids (GCs) therapy is the mainstay of treatment especially for active moderate to severe patients, which needs evidence-based support.
METHOD
We searched all the randomized controlled trials (RCTs) involving corticosteroid treatment for patients diagnosed with GO from EMBASE, Medline, and the Cochrane library and then conducted a system review and meta-analysis. The electronic search covered the period from April 1966 to March 2018.
RESULT
Twenty-nine trials were included. GCs were proved to be beneficial for GO patients [response rate, risk ratio (RR) = 1.72, 95% confidence interval (CI): 1.28~2.31, P=0.0003], and intravenous corticosteroids worked significantly better than oral corticosteroids as ever reported. When compared with the single treatment of GCs, the combination of radiotherapy and GCs showed similar effects on response rate (RR=1.25, 95%CI: 0.91~1.73). A study proved the advantage of mycophenolate mofetil over GCs in three outcomes (response rate, RR=0.74, 95%CI: 0.63~0.88). Additional treatments such as technetium-99 methylene diphosphate (Tc-MDP) or cyclosporine enhanced the effect of GCs on proptosis reduction, respectively (P<0.00001 and P=0.02).
CONCLUSION
Our meta-analysis confirmed the effects of GCs in the management of GO and intravenous GCs are proved to be better than oral GCs as ever reported. Combination of radiotherapy and GCs did not enhance the effects of GCs. However, if proptosis is the main issue, combination of Tc-MDP or cyclosporine with GCs may be taken into consideration. The reported advantages of mycophenolate mofetil over GCs are noteworthy and need more RCTs to confirm.
Topics: Adrenal Cortex Hormones; Cyclosporine; Graves Ophthalmopathy; Humans; Mycophenolic Acid; Randomized Controlled Trials as Topic
PubMed: 30596092
DOI: 10.1155/2018/4845894 -
Drugs in R&D Dec 2018Globally, enteric-coated mycophenolate sodium (EC-MPS) is replacing mycophenolate mofetil (MMF) in maintenance immunosuppressant regimens. The predominant reason for...
BACKGROUND
Globally, enteric-coated mycophenolate sodium (EC-MPS) is replacing mycophenolate mofetil (MMF) in maintenance immunosuppressant regimens. The predominant reason for conversion is the purported improvement in gastrointestinal (GI) quality of life. This paper considers the level of bias associated with studies comparing EC-MPS and MMF for GI-related improvement and provides insight into whether conversion is supported by evidence.
METHODS
Using a pre-determined protocol, a literature search was conducted. Full-text review, data extraction and risk of bias analysis was conducted by two independent authors using the Cochrane domain-based evaluation of risk of bias. The review was reported according to the preferred reporting items for systematic reviews and meta-analyses.
RESULTS
Twenty-nine studies were included in risk of bias analysis. Of these, only three were deemed a low risk of bias. Across these three studies, there were no statistically significant differences in the proportion of GI-related adverse events nor was there a significant difference in the GI-related quality of life between EC-MPS- and MMF-treated patients in these data.
CONCLUSION
There was a high risk of bias across the 29 studies investigating conversion from MMF to EC-MPS for potential improvement in GI-related quality of life. The consolidated results of the three studies with low risk of bias suggest no evidence to convert patients stabilised on MMF. If a patient experiences GI-related adverse events whilst taking MMF, other methods should be explored before conversion to EC-MPS.
Topics: Gastrointestinal Tract; Humans; Immunosuppressive Agents; Mycophenolic Acid; Quality of Life; Tablets, Enteric-Coated
PubMed: 30426342
DOI: 10.1007/s40268-018-0254-8 -
The Cochrane Database of Systematic... Jun 2018Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012.
OBJECTIVES
Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens?
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
SELECTION CRITERIA
Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included.
DATA COLLECTION AND ANALYSIS
Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE.
MAIN RESULTS
In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.Maintenance therapyNine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates.
AUTHORS' CONCLUSIONS
In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.
Topics: Adult; Azathioprine; Calcineurin; Child; Cyclophosphamide; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Maintenance Chemotherapy; Male; Mycophenolic Acid; Randomized Controlled Trials as Topic; Recurrence; Tacrolimus
PubMed: 29957821
DOI: 10.1002/14651858.CD002922.pub4 -
Rheumatology International Jul 2017The purpose of this study is to assess the effectiveness of mycophenolate mofetil (MMF) in treating Takayasu arteritis (TA) patients. Embase, Cochrane Library, Pubmed,... (Meta-Analysis)
Meta-Analysis Review
The purpose of this study is to assess the effectiveness of mycophenolate mofetil (MMF) in treating Takayasu arteritis (TA) patients. Embase, Cochrane Library, Pubmed, Clinicaltrials. Gov and three Chinese literature databases (VIP, CNKI, WanFang) were searched; randomized-controlled trials and observational studies that compared the efficacy before and after treatment with MMF were included. The efficacy outcomes were disease activity, the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) values and steroid dosage. The results were expressed as mean differences with 95% confidence intervals. Compared with the baseline, there were significant reductions in the ESR (-14.92 [25.35, -4.48]), CRP values (-12.99 [-23.29, -2.68]) and the steroid dosage (-17.64 [-24.89, -10.4]) after the addition of MMF, and the disease tended to stabilize. Therefore, MMF might be an alternative immunosuppressive drug for TA for the control of disease activity and to taper the steroid dosage.
Topics: Adolescent; Adult; Biomarkers; Blood Sedimentation; C-Reactive Protein; Chi-Square Distribution; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Male; Mycophenolic Acid; Steroids; Takayasu Arteritis; Treatment Outcome; Young Adult
PubMed: 28364217
DOI: 10.1007/s00296-017-3704-7 -
The Cochrane Database of Systematic... Mar 2017As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
As part of liver transplantation, immunosuppression (suppressing the host immunity) is given to prevent graft rejections resulting from the immune response of the body against transplanted organ or tissues from a different person whose tissue antigens are not compatible with those of the recipient. The optimal maintenance immunosuppressive regimen after liver transplantation remains uncertain.
OBJECTIVES
To assess the comparative benefits and harms of different maintenance immunosuppressive regimens in adults undergoing liver transplantation through a network meta-analysis and to generate rankings of the different immunosuppressive regimens according to their safety and efficacy.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and trials registers until October 2016 to identify randomised clinical trials on immunosuppression for liver transplantation.
SELECTION CRITERIA
We included only randomised clinical trials (irrespective of language, blinding, or publication status) in adult participants undergoing liver transplantation (or liver retransplantation) for any reason. We excluded trials in which participants had undergone multivisceral transplantation or participants with established graft rejections. We considered any of the various maintenance immunosuppressive regimens compared with each other.
DATA COLLECTION AND ANALYSIS
We performed a network meta-analysis with OpenBUGS using Bayesian methods and calculated the odds ratio, rate ratio, and hazard ratio (HR) with 95% credible intervals (CrI) based on an available-case analysis, according to National Institute of Health and Care Excellence Decision Support Unit guidance.
MAIN RESULTS
We included a total of 26 trials (3842 participants) in the review, and 23 trials (3693 participants) were included in one or more outcomes in the review. The vast majority of the participants underwent primary liver transplantation. All of the trials were at high risk of bias, and all of the evidence was of low or very low quality. In addition, because of sparse data involving trials at high risk of bias, it is not possible to entirely rely on the results of the network meta-analysis. The trials included mainly participants undergoing primary liver transplantation of varied aetiologies. The follow-up in the trials ranged from 3 to 144 months. The most common maintenance immunosuppression used as a control was tacrolimus. There was no evidence of difference in mortality (21 trials; 3492 participants) or graft loss (15 trials; 2961 participants) at maximal follow-up between the different maintenance immunosuppressive regimens based on the network meta-analysis. In the direct comparison, based on a single trial including 222 participants, tacrolimus plus sirolimus had increased mortality (HR 2.76, 95% CrI 1.30 to 6.69) and graft loss (HR 2.34, 95% CrI 1.28 to 4.61) at maximal follow-up compared with tacrolimus. There was no evidence of differences in the proportion of people with serious adverse events (1 trial; 719 participants), proportion of people with any adverse events (2 trials; 940 participants), renal impairment (8 trials; 2233 participants), chronic kidney disease (1 trial; 100 participants), graft rejections (any) (16 trials; 2726 participants), and graft rejections requiring treatment (5 trials; 1025 participants) between the different immunosuppressive regimens. The network meta-analysis showed that the number of adverse events was lower with cyclosporine A than with many other immunosuppressive regimens (12 trials; 1748 participants), and the risk of retransplantation (13 trials; 1994 participants) was higher with cyclosporine A than with tacrolimus (HR 3.08, 95% CrI 1.13 to 9.90). None of the trials reported number of serious adverse events, health-related quality of life, or costs.
FUNDING
14 trials were funded by pharmaceutical companies who would benefit from the results of the trial; two trials were funded by parties who had no vested interest in the results of the trial; and 10 trials did not report the source of funding.
AUTHORS' CONCLUSIONS
Based on low-quality evidence from a single small trial from direct comparison, tacrolimus plus sirolimus increases mortality and graft loss at maximal follow-up compared with tacrolimus. Based on very low-quality evidence from network meta-analysis, we found no evidence of difference between different immunosuppressive regimens. We found very low-quality evidence from network meta-analysis and low-quality evidence from direct comparison that cyclosporine A causes more retransplantation compared with tacrolimus. Future randomised clinical trials should be adequately powered; performed in people who are generally seen in the clinic rather than in highly selected participants; employ blinding; avoid postrandomisation dropouts or planned cross-overs; and use clinically important outcomes such as mortality, graft loss, renal impairment, chronic kidney disease, and retransplantation. Such trials should use tacrolimus as one of the control groups. Moreover, such trials ought to be designed in such a way as to ensure low risk of bias and low risks of random errors.
Topics: Adult; Azathioprine; Bayes Theorem; Cyclosporine; Drug Therapy, Combination; Everolimus; Glucocorticoids; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Network Meta-Analysis; Odds Ratio; Retreatment; Sirolimus; Tacrolimus; Transplantation Immunology
PubMed: 28362060
DOI: 10.1002/14651858.CD011639.pub2 -
Seminars in Arthritis and Rheumatism Aug 2017We aimed to summarize the evidence examining factors that predict differential response to mycophenolate mofetil (MMF) in systemic lupus erythematosus (SLE).
OBJECTIVES
We aimed to summarize the evidence examining factors that predict differential response to mycophenolate mofetil (MMF) in systemic lupus erythematosus (SLE).
METHODS
Systematic searches of randomized clinical trials (RCT) to identify predictors of the effects of MMF (moderators), and cohort studies to explore prognostic factors associated with MMF outcomes (response, relapse, or adverse events) were performed. Two reviewers independently assessed the methodological quality of RCTs using the Cochrane Collaboration risk of bias tool and cohort studies using the QUality In Prognosis Studies tool. The quality of subgroup analysis, providing evidence for moderation, was evaluated. The Grading of Recommendations Assessment, Development, and Evaluation working group approach summarized the quality of evidence (QoE), considering the risk of bias, imprecision, inconsistency, indirectness, and publication bias.
RESULTS
From 26 studies (13 from 7 RCTs and 13 cohort studies) we found low QoE evidence for Black/Hispanic race/ethnicity predicting better renal responses to MMF in lupus nephritis (LN) from one RCT. There was low QoE evidence from cohort studies that a higher baseline creatinine and membranous features on renal biopsy were associated with poorer responses in LN. There was very low QoE for other moderators or prognostic factors associated with MMF treatment outcomes. QoE from RCTs was affected by exploratory or insufficient evidence from subgroup analysis and in both study types high risk of bias, indirectness and imprecision also affected QoE.
CONCLUSIONS
In SLE, evidence for predictors of response to MMF is limited and none can be recommended for use in routine clinical practice. Specific studies of predictors measured at baseline and during treatment are needed with a priori hypotheses based on preliminary evidence to date and with sufficient power to determine which factors can be employed in clinical decision making.
Topics: Humans; Immunosuppressive Agents; Kidney; Lupus Erythematosus, Systemic; Lupus Nephritis; Mycophenolic Acid; Patient-Centered Care; Prospective Studies; Randomized Controlled Trials as Topic; Retrospective Studies; Treatment Outcome
PubMed: 28325471
DOI: 10.1016/j.semarthrit.2017.01.009 -
The Cochrane Database of Systematic... Oct 2016The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond may be... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The majority of children who present with their first episode of nephrotic syndrome achieve remission with corticosteroid therapy. Children who fail to respond may be treated with immunosuppressive agents including calcineurin inhibitors (cyclosporin or tacrolimus) and with non-immunosuppressive agents such as angiotensin-converting enzyme inhibitors (ACEi). Optimal combinations of these agents with the least toxicity remain to be determined. This is an update of a review first published in 2004 and updated in 2006 and 2010.
OBJECTIVES
To evaluate the benefits and harms of different interventions used in children with idiopathic nephrotic syndrome, who do not achieve remission following four weeks or more of daily corticosteroid therapy.
SEARCH METHODS
We searched Cochrane Kidney and Transplant's Specialised Register (up to 2 March 2016) through contact with the Information Specialist using search terms relevant to this review.
SELECTION CRITERIA
RCTs and quasi-RCTs were included if they compared different immunosuppressive agents or non-immunosuppressive agents with placebo, prednisone or other agent given orally or parenterally in children aged three months to 18 years with SRNS.
DATA COLLECTION AND ANALYSIS
Two authors independently searched the literature, determined study eligibility, assessed risk of bias and extracted data. For dichotomous outcomes, results were expressed as risk ratios (RR) and 95% confidence intervals (CI). Data were pooled using the random effects model.
MAIN RESULTS
Nineteen RCTs (820 children enrolled; 773 evaluated) were included. Most studies were small. Eleven studies were at low risk of bias for allocation concealment and only four studies were at low risk of performance bias. Fifteen, eight and 10 studies were at low risk of detection bias, attrition bias and reporting bias respectively. Cyclosporin when compared with placebo or no treatment significantly increased the number of children who achieved complete remission. However this was based on only eight children who achieved remission with cyclosporin compared with no children who achieved remission with placebo/no treatment in three small studies (49 children: RR 7.66, 95% CI 1.06 to 55.34). Calcineurin inhibitors significantly increased the number with complete or partial remission compared with IV cyclophosphamide (2 studies, 156 children: RR 1.98, 95% CI 1.25 to 3.13; I = 20%). There was no significant differences in the number who achieved complete remission between tacrolimus versus cyclosporin (1 study, 41 children: RR 0.86, 95% CI 0.44 to 1.66), cyclosporin versus mycophenolate mofetil plus dexamethasone (1 study, 138 children: RR 2.14, 95% CI 0.87 to 5.24), oral cyclophosphamide with prednisone versus prednisone alone (2 studies, 91 children: RR 1.06, 95% CI 0.61 to 1.87), IV versus oral cyclophosphamide (1 study, 11 children: RR 3.13, 95% CI 0.81 to 12.06), IV cyclophosphamide versus oral cyclophosphamide plus IV dexamethasone (1 study, 49 children: RR 1.13, 95% CI 0.65 to 1.96), and azathioprine with prednisone versus prednisone alone (1 study, 31 children: RR 0.94, 95% CI 0.15 to 5.84). One study found no significant differences between three agents (cyclophosphamide, mycophenolate mofetil, leflunomide) used in combination with tacrolimus and prednisone. One study found no significant difference in the percentage reduction in proteinuria (31 children: -12; 95% CI -73 to 110) between rituximab with cyclosporin/prednisolone and cyclosporin/prednisolone alone. Two studies reported ACEi significantly reduced proteinuria.
AUTHORS' CONCLUSIONS
To date RCTs have demonstrated that calcineurin inhibitors increase the likelihood of complete or partial remission compared with placebo/no treatment or cyclophosphamide. For other regimens assessed, it remains uncertain whether the interventions alter outcomes because the certainty of the evidence is low. Further adequately powered, well designed RCTs are needed to evaluate other regimens for children with idiopathic SRNS. Since SRNS represents a spectrum of diseases, future studies should enrol children from better defined groups of patients with SRNS.
Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Child; Child, Preschool; Cyclophosphamide; Cyclosporine; Dexamethasone; Drug Resistance; Glucocorticoids; Humans; Immunosuppressive Agents; Infant; Isoxazoles; Leflunomide; Mycophenolic Acid; Nephrotic Syndrome; Prednisone; Randomized Controlled Trials as Topic; Remission Induction
PubMed: 27726125
DOI: 10.1002/14651858.CD003594.pub5 -
Health Technology Assessment... Aug 2016End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal... (Review)
Review
BACKGROUND
End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival.
OBJECTIVES
To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation.
METHODS
Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death.
RESULTS
Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY.
LIMITATIONS
For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled.
FUTURE WORK
High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome.
CONCLUSION
Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY.
STUDY REGISTRATION
This study is registered as PROSPERO CRD42014013189.
FUNDING
The National Institute for Health Research Health Technology Assessment programme.
Topics: Abatacept; Antibodies, Monoclonal; Antilymphocyte Serum; Basiliximab; Bayes Theorem; Cost-Benefit Analysis; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Models, Economic; Mycophenolic Acid; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; Technology Assessment, Biomedical
PubMed: 27578428
DOI: 10.3310/hta20620 -
American Journal of Nephrology 2016Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients.
METHODS
Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts.
RESULTS
Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (Cmax) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC(0-t)) fell within the required range (0.80-1.25) for cyclosporine (Cmax 0.91; 90% CI 0.86-0.95; and AUC(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (Cmax 1.17; 90% CI 1.09-1.24; and AUC(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (Cmax 0.98; 90% CI 0.96-1.01; and AUC(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death.
CONCLUSIONS
Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed.
Topics: Biological Availability; Cyclosporine; Drugs, Generic; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Tacrolimus; Therapeutic Equivalency
PubMed: 27576318
DOI: 10.1159/000449020