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Tacrolimus and cyclosporine are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of cyclosporine and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane Controlled Trials Register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection, and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and quality-adjusted life years gained and incremental cost-effectiveness. Altogether, 6137 patients from 27 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of patient mortality, graft loss, acute rejection, and hypercholesterolemia. Nevertheless, tacrolimus increased the risk of new-onset diabetes. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events following renal transplant. Tacrolimus is an effective and safe immunosuppressive agent and it may be more cost-effective than cyclosporine for the primary prevention of graft rejection in renal transplant recipients. However, new-onset diabetes should be closely monitored during the medication period.

Anti-rejection regimens for renal transplants have changed dramatically during the past 20 years, but there are few long-term studies relating cost, mortality, or graft failure simultaneously to disease-pharmacotherapy couplets. We analyzed US Renal Data System data on a matched-pair cohort of first, single organ kidney transplants from 1998 through 2002 over up to 5 years following transplantation for patients on tacrolimus or low-dose cyclosporine, stratifying by whether the recipient had pre-existing or new onset diabetes. Kaplan-Meier survival curves show mortality and survival differences associated with diabetes, but no additional incremental effects of immune suppression regimen. Significant cost increases are reported for patients receiving tacrolimus above and beyond the extra costs associated with diabetes., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Background: The use of bioequivalent generic ciclosporin is a cost-effective alternative to non-generic ciclosporin in renal transplant patients. This study aims to explore the efficacy, safety and tolerability of Equoral®, a generic ciclosporin, in adult de novo renal transplant patients., Material/methods: This was a multicentre, open label, phase IV clinical study consisting of a 6-month treatment and 3-month follow-up periods. Patients underwent renal transplantation supported by an immunosupressive regimen of azathioprine (or mofetil mycophenylate [MMF]), prednisolone and Equoral® (10 mg/kg/day, given 12 hours before patients' surgical procedure, and a maintenance ciclosporin dose of 4-6 mg/kg/day thereafter). The primary endpoint was the rate of occurrence of acute graft rejection over the 6-month period after renal transplantation., Results: A total of 54 patients were enrolled and constituted the intention-to-treat/safety population, while 52 patients forming the per-protocol population were assessed for efficacy. There were 13 episodes of acute graft rejection reported in 12 patients, and two of these episodes resulted in withdrawal from the study. The probability of acute rejection in patients was less then 24% for the duration of the study including the observation period which is within the usual range. There were no deaths and one graft loss during the study, and the safety and tolerability profile reported was typical of that of ciclosporin in use in de-novo renal transplant patients., Conclusions: The use of the generic ciclosporin Equoral® is effective and is associated with the usual safety and tolerability profile of ciclosporin when used as the calcineurin-inhibitor component of an immunosuppressive regimen in de novo renal transplant patients.

In Brazil, the Unified National Health System (SUS) is responsible for the majority of kidney transplants. To maintain these interventions, the guidelines recommend the use of cyclosporine or tacrolimus, associated with corticosteroids and azathioprine or mycophenolate. Taking the perspective of the National Health System, an economic analysis was performed on the outpatient and hospital resources and medicines used by patient and therapeutic group. A cohort was constructed from 2000 to 2004, with 5,174 kidney transplant patients in use of cyclosporine or tacrolimus, identified by probabilistic record linkage from the National Health System. The cohort included 4,015 patients in use of cyclosporine and 1,159 using tacrolimus. The majority were males, age < 38 years, with nephritis, cardiovascular diseases, and indeterminate causes as the most frequent primary diagnoses. After 48 months of follow-up, the expenditures were higher for kidney transplants in hospitals in the Northeast, cadaver donors, patients in dialysis > 24 months before the transplant, and in the tacrolimus group. Total hospital and outpatient costs and expenditure on medication were higher in patients on tacrolimus as compared to the cyclosporine group.

Objective: The purpose of this study was to evaluate the cost-effectiveness of sirolimus compared with cyclosporin for the postsurgical management of renal transplant recipients, from the perspective of the UK National Health Service and the Personal Social Service., Methods: A discrete event stochastic simulation model was developed to evaluate both cost-effectiveness and cost utility over 10 and 20 years after transplant using historical data on 937 renal transplant recipients from the University Hospital of Wales in Cardiff, United Kingdom. The simulation was designed to forecast the incidence of acute rejection events, graft failure, retransplant, frequency of hemodialysis (HD) and peritoneal dialysis (PD), and death. Cox proportional hazard models were derived from historical transplant data, in which 1-, 2-, and 3-year post-transplant serum creatinine levels were used as the key drivers for predicting graft success and survival. Costs were reported as year-2003 UK pounds sterling (1 UK pound = US $1.76). Probabilistic sensitivity analysis was conducted and results reported with particular attention to 2 threshold values, 30,000/QALY and 20,000/QALY RESULTS: Over a 10-year time horizon, treatment with sirolimus was projected to produce a gain of 0.60 discounted year of functioning graft with a cost savings of 276 UK pounds per patient. Over a 20-year time horizon these benefits increased to 1.59 discounted years of functioning graft and a cost savings of 7405 UK pounds per patient. Using sensitivity analysis of the 10-year model, the only factors found to cause the probability of exceeding a 30,000 ceiling to be >5% were the proportion of subjects maintaining continuous graft function and the use of low-dose cyclosporin. With the 20-year model, sirolimus maintained cost-effectiveness across most scenarios in sensitivity analysis., Conclusions: In this model analysis, sirolimus was cost-effective compared with cyclosporin for 10 to 20 years after renal transplantation in the United Kingdom, from the perspective of the UK National Health Service and Personal Social Service.

Background: Monitoring of microemulsion ciclosporin (cyclosporine; Neoral) by 2-hour post-dose drug concentrations (C2) is an accurate measure of ciclosporin absorption efficiency and exposure, and appears superior to trough (C0) monitoring for prediction of rejection risk. A predictive decision model was used to determine if this approach also reduces total treatment costs in the first 12 months after renal transplantation., Methods: Parameter estimates for key clinical events were derived from the literature and from prospective pharmacokinetic studies comprising 234 adult HLA-non-identical renal graft recipients at seven Canadian centres. Patients were treated with microemulsion ciclosporin (Neoral), corticosteroids and azathioprine or mycophenolate mofetil. Using the perspective of the Canadian healthcare provider, total treatment costs for the C2 versus the C0 strategy were modelled over 12 months, and then remodelled using conservative estimates to extend the timeframe to 5 years. Health resources were valued in 1999 Canadian dollars., Results: The incidence of acute rejection was estimated to be 25% at 1 year in patients monitored by C0 and 18% in those monitored by C2. Patient survival was considered to be independent of monitoring strategy, and graft loss was predicted to be 1.4% lower in the C2 group. The studies suggested no important differences in comorbidity and the costs of C0 and C2 monitoring and ambulatory-based adverse events were held equivalent. Using these inputs, the average cost per patient for the first year post-transplant was Can dollars 46,857 for C0 monitoring and Can dollars 45,306 for C2 monitoring, rising to Can dollars 146,879 and Can dollars 142,569 after 5 years. The predicted cost for initial hospitalisation was Can dollars 11,280 for C0 and Can dollars 10,806 for C2 monitoring. The cost of maintenance immunosuppressive drug use, graft loss and dialysis was Can dollars 19,098 in the C0 group and Can dollars 18,612 in the C2 group, while acute rejection treatment costs were Can dollars 2169 and Can dollars 1577, respectively. An additional Can dollars 14,310 was consumed by other events, including repeat hospitalisation, for each group. Sensitivity analysis indicated that the most influential parameters affecting savings due to C2 monitoring were a reduction in the duration of initial and follow-up hospitalisations and reduced risks of acute rejection and subsequent graft loss., Conclusions: Compared with traditional trough concentration monitoring, ciclosporin monitoring at 2 hours post-dose produced a predicted saving of Can dollars 1551 during the first year after renal transplant. Although modelling assumptions become more restrictive over time, this projection allows a preliminary assessment of the long-term economic impact of the routine use of C2 monitoring.

Background: The economic impact of therapies has increasingly become part of the clinical decision-making process. Costs associated with kidney transplantation are substantial and economic evaluations are useful in identifying immunosuppressive regimens that yield optimal clinical and economic benefits., Methods: Utilisation of health care resources during the first 6-months after renal transplantation was examined in 557 kidney transplant recipients participating in a European, multicentre, randomised, parallel group study that compared the efficacy and safety of a tacrolimus-based regimen versus a cyclosporin-microemulsion-based regimen. Cost-minimisation and cost-effectiveness analyses were conducted from an Italian hospital perspective, including direct medical costs only (e.g. medication, hospitalisation)., Results: The incidence of acute rejection was significantly lower in the tacrolimus group than in the cyclosporin microemulsion (ME) group (32.5% versus 51.3%; p<0.001). Patient and graft survival were similar in both treatment groups. Renal transplant recipients receiving tacrolimus-based immunosuppression had lower utilisation of health care resources and lower total costs per patient than cyclosporin-ME treated patients. When surviving patients with a rejection-free graft were analysed, tacrolimus therapy was cost-saving, since it was both more effective (18.8% difference in the incidence of acute rejection; 95%CI 10.7%-26.8%; p<0.001) and less costly than cyclosporin-ME based therapy (cost difference euro9918). The costs per patient with a functioning graft were euro2305, the costs per surviving patient were euro1892 lower in tacrolimus treated patients. Sensitivity analyses using the key cost-drivers (hospitalisation, study drug, and concomitant medication) found the cost advantage of tacrolimus was maintained., Conclusion: In the first 6 months after renal transplantation, tacrolimus-based therapy was less costly than cyclosporin-ME based therapy. When surviving patients with a rejection-free graft were considered, tacrolimus was the dominant therapy.

We assessed the frequency and costs of hospitalizations in patients receiving tacrolimus (FK506) compared with patients receiving cyclosporine A for immunosuppression during 1 year after kidney transplantation. Four hundred twelve cadaveric kidney transplant recipients were randomized onto a phase III, prospective, multicenter, clinical trial. Hospital billing data were collected for 1 year posttransplantation. Total inpatient costs were calculated from billed charges and standardized to 1995 US dollars. Medical resource utilization rates and inpatient costs were compared between treatment groups using unpaired Student's t-tests. Complete billing data (transplantation and all posttransplantation hospitalizations) were available for 65% (268 of 412) of the study patients. Among tacrolimus and cyclosporine patients with complete billing data, the rates of allograft rejection were 32% and 47%, respectively (P=0.009), and the rates of rehospitalization during the year after transplantation were 53% and 63%, respectively (P=0.080). The mean per-episode rehospitalization costs were significantly lower among tacrolimus-treated patients compared with cyclosporine-treated patients ($7,495 v $11,497; P=0.031), and the mean total rehospitalization costs were significantly lower in the tacrolimus group compared with the cyclosporine group ($8,550 v $14,869; P=0.029). In addition, the total 1-year hospitalization costs (including transplantation and posttransplantation hospitalizations) were significantly lower in the tacrolimus group compared with the cyclosporine group ($53,435 v $61,191; P=0.046). Compared with cyclosporine-based immunosuppression, tacrolimus-based immunosuppression for kidney transplant recipients was associated with a significantly lower rate of rejection, which was associated with significantly lower per-episode rehospitalization costs, lower total 1-year rehospitalization costs, and lower total 1-year hospitalization costs.

The objective of this retrospective analysis was the evaluation of direct/medical costs of immunosuppressive treatment with tacrolimus (FK 506) and cyclosporin A in liver transplantation. The analysis was based on data from the german centers of a pan-European clinical trial where all given drugs as well as all serious events, graft reactions and the number of transplantations were documented. The costs of the treatment with tacrolimus were DM 158,276 per patient; those for cyclosporin A were DM 176,392. The main reason for the difference was the amount and types of drugs administered. The direct costs per surviving patient were in the tacrolimus group DM 192,314 (20 of 113 patients) and in the cyclosporin A group DM 227,669 (25 of 111 patients). The cost-effectiveness ratio for tacrolimus is about 15.5% better than for cyclosporin A.

Since its discovery in 1970, and introduction into clinical practice in 1978, cyclosporin has become the most important immunosuppressive drug used to prevent organ transplant rejection. This has been achieved by virtue of the improved graft survival rates and adverse effect profiles in patients when compared with that of the older agents. Cyclosporin is substantially more expensive (both to provide and to monitor) however, and the magnitude of these costs may preclude its use, particularly where the transplant recipient is required to pay. Cyclosporin has a complex pharmacokinetic profile with poor absorption, extensive metabolism to more than 30 metabolites and considerable inter- and intrapatient variability. Many transplant centres routinely use drugs ("cyclosporin-sparing agents') to allow a reduction in the dosage of cyclosporin while maintaining therapeutic blood cyclosporin concentrations. The use of a second drug to affect the pharmacokinetic profile of a primary drug is not new, but the use of cyclosporin-sparing agents is a departure from previous practices in that this coprescription is primarily for economic reasons. The decision to use these agents (and the choice of agent) is based upon economic and other factors including the extent of the cyclosporin-sparing effect, the potential for additional therapeutic benefit and/or adverse effects. The coprescription of cyclosporin-sparing agents is ethically more acceptable where the transplant recipient is the economic beneficiary but where the savings accrue to a third party it is more difficult. Benefits to the community at large must be balanced against the risk of adverse effects to the patient. The use of cyclosporin-sparing agents may reduce compliance and hence, jeopardise transplant and/or recipient outcomes. The transplant recipient must be informed about the reasons for their use and advised to consult an experienced physician or pharmacist before altering the established drug regimen.