Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data.

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.

Cost-Effectiveness Analysis of Pharmacological Treatment for Adult Kidney Transplant Recipients in Colombia.

OBJECTIVES: To evaluate cost-effective pharmacological treatment in adult kidney transplant recipients from the perspective of the Colombian health system. METHODS: A decision tree model for the induction phase and a Markov model for the maintenance phase were built. A review of the clinical literature was conducted to extract probabilities, and the life-years were used as the outcome. Costs were calculated using the administrative databases. The evaluating treatment schemes are organized by groups of evidence with direct comparisons. RESULTS: In the induction phase, anti-thymocyte immunoglobulin+ methylprednisolone is dominant, more effective, and less expensive, compared with basiliximab+methylprednisolone. In the maintenance phase, azathioprine (AZA) is dominant in contrast to mycophenolate mofetil (MFM) both with cyclosporine (CIC)+ corticosteroids (CE); CIC is dominant relative to sirolimus (SIR) and tacrolimus (TAC) (both with MFM+CE or AZA+CE), and TAC is dominant compared with SIR (in addition with MFM+CE or mycophenolate sodium [MFS]+CE); MFM is dominant in relation to MFS and everolimus, and SIR is more effective MFM but it does not exceed the threshold (in sum with TAC+CE); MFS and MFM are dominant relative to everolimus, and SIR is more effective than MFM, but it does not exceed the threshold (in addiction with CIC+CE); MFM is dominant in relation to TAC (in sum with SIR+CE), and CIC+AZA+CE is dominant in relation to TAC+MFM+CE. CONCLUSIONS: The base-case results for all evidence groups are consistent with the different sensitivity analyses.

Cost-effectiveness of once-daily vs twice-daily tacrolimus among Hispanic and Black kidney transplant recipients.

BACKGROUND: Tacrolimus is a first-line immunosuppressive therapy to prevent rejection and graft failure in kidney transplant recipients. Once-daily extended-release tacrolimus tablets (LCPT) have been shown to be efficacious, particularly for Hispanic and Black patient subpopulations who are rapid metabolizers, but is more costly than twice-daily immediate-release tacrolimus (IR-Tac). OBJECTIVE: To evaluate the cost-effectiveness of LCPT during the first year of treatment vs IR-Tac in kidney transplant recipients who are Hispanic or Black. METHODS: A decision analytic model from a US payer perspective was developed using (1) subgroup outcomes data pooled from two phase 3 clinical trials that compared LCPT and IR-Tac, and (2) direct costs from real-world data sources (ie, costs of LCPT and IR-Tac treatments, biopsy-proven acute rejection, treatment-related serious adverse events [SAEs], graft failure, and consequent dialysis). The primary outcome was cost per successfully treated patient, defined as having a functioning graft after 1 year and without treatment-related SAEs. Probabilistic sensitivity analyses established distributions for cost and outcomes estimates, and a series of one-way sensitivity analyses identified parameters that had the most effect on results. RESULTS: Total overall cost for the Hispanic group was $14,765 for LCPT and $12,416 for IR-Tac, and total cost in the Black group was $16,626 for LCPT and $9,871 for IR-Tac. Total overall effectiveness of LCPT and IR-Tac was 88.32% and 84.75% in the Hispanic group and 93.24% and 85.78% in the Black group, respectively. The incremental cost-effectiveness ratio (ICER) for using LCPT over IR-Tac during the first year of treatment in the Hispanic group was $65,643 per additional successfully treated patient. The ICER for the Black group was $90,458. The single parameter having the most impact on results in both groups was the probability of a treatment-related SAE in IR-Tac, which accounted for 49% of variation in results in the Hispanic group and 46% in the Black group. CONCLUSIONS: Overall results for both groups show that LCPT is incrementally more costly and more effective compared with IR-Tac, indicating a trade-off scenario. LCPT is a cost-effective strategy if a decision makers' willingness to pay for 1 additional successfully treated patient exceeds the ICER and must be weighed against the costs of graft loss, continuing dialysis, and potential retransplant. This study provides a foundation for further research to update and expand inputs as more data become available to improve real-world relevance and decision making. DISCLOSURES: This study was funded by Veloxis Pharmaceuticals, Inc., which provided clinical trial file data and nonbinding feedback on the model structure, data interpretation, clinical expertise, manuscript review, and areas of publication interest (ie, managed care). Hurwitz, Grizzle, Villa Zapata, and Malone received grant funding from Veloxis Pharmaceuticals, Inc., through University of Arizona to conduct research and analysis for this study. Tyler is employed by Veloxis Pharmaceuticals, Inc. Some of the data reported and used in this research were available from the US Renal Data System, the US Bureau of Labor Statistics, and the Agency for Healthcare Research and Quality's Healthcare Cost and Utility Project. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government.

Cost-effectiveness of tacrolimus for the treatment of moderate-to-severe lupus nephritis in China.

Aim: Therapy for lupus nephritis (LN) requires treatment with immunosuppressive regimens, often including intravenous cyclophosphamide (IVCY), mycophenolate mofetil (MMF) or azathioprine. Additionally, tacrolimus (original form or generic) is recommended to treat LN patients in Asia, including China. However, the cost-effectiveness of tacrolimus therapy has not previously been assessed. We aimed to estimate the cost-effectiveness of tacrolimus in the treatment of moderate-to-severe LN versus standard therapies in China. Materials & methods: This cost-effectiveness model combined a decision-tree/Markov-model structure to map transitions between health states during induction and maintenance treatment phases. Induction with tacrolimus, IVCY or MMF, was followed by tacrolimus, MMF or azathioprine maintenance. Results: According to the model, during induction, complete remission rates were higher with tacrolimus versus IVCY (relative risk 1.40 vs IVCY [deterministic sensitivity analysis minimum 0.92, maximum 2.13]) and time to response was shorter. Relapse rates were lower with tacrolimus versus azathioprine or MMF during maintenance. Tacrolimus induction and maintenance was the most cost-effective regimen, incurring the lowest total costs (CN¥180,448) with the highest quality-adjusted life-years. Conclusion: The model demonstrated that tacrolimus use in both induction and maintenance therapy may be an efficacious and cost-effective treatment for LN in China.

Effect of CYP3A5 genotype on hospitalization cost for kidney transplantation.

Background Dosage quantities of tacrolimus (TAC) vary according to cytochrome P450 3A5 (CYP3A5) genotype. Genotyping is expected to optimize the response to TAC response and to minimize adverse effects. In Thailand, kidney transplantation is reimbursable with the same diagnosis-related group payment regardless of patient's CYP3A5 genotype. Objective This study aimed to determine the costs of TAC administration, therapeutic drug monitoring (TDM), and hospitalization for kidney transplantation across CYP3A5*1/*1, *1/*3, and *3/*3 genotypes. Setting A single transplant center in a university hospital. Method This is an observational study that collected data from patients pooled from both arms of a randomized controlled trial that tested initial doses of TAC. Main outcome measure TAC and TDM cost and hospitalization cost for transplantation were compared between genotypes. Results The CYP3A5*1/*1 patients had the highest median combined TAC-TDM cost and hospitalization cost ($1062 and $9097), followed by CYP3A5*1/*3 ($859 and $6467) and CYP3A5*3/*3 patients ($761 and $5604). The CYP3A5*1/*1 patients had a higher hospitalization cost by $2787 over the CYP3A5*1/*3 patients, despite marginal significance. The CYP3A5*1/*1 patients had a significantly higher cost of TAC plus TDM (by $309) and hospitalization cost (by $3275) than the CYP3A5*3/*3 patients. Both study costs were significantly higher in patients with delayed graft functioning than in patients with instant or slow graft functioning. Conclusion The benefits of genotype detection in patients with CYP3A5*1/*1 should be considered for a higher reimbursement rate because of the substantial differences in total hospitalization cost for kidney transplantation among patients with different CYP3A5 genotypes.

Healthcare utilization and costs with fixed-source versus variable-source tacrolimus in patients receiving a kidney transplant.

AIMS: Switching drug manufacturers in transplant patients may require an increased intensity of therapeutic monitoring, leading to additional healthcare visits, associated laboratory tests, and perhaps hospitalizations. As real-world studies examining the interchangeability of tacrolimus from different manufacturers are limited, the purpose of this study was to examine the healthcare resource utilization (HRU) and economic impact of tacrolimus-switching in kidney transplantation. MATERIALS AND METHODS: This cross-sectional, retrospective study examined HRU and healthcare costs (HCCs) among patients with a kidney transplant who were prescribed tacrolimus from fixed-source (FS) vs variable-source (VS) manufacturers using claims data from the large US health plan Humana from October 1, 2012, to December 31, 2013. RESULTS: Overall, 1,024 patients were identified (FS: n = 674, 66%; VS: n = 350, 34%). The number of therapeutic drug monitoring (TDM) events for the VS group was 13% greater than for the FS group after controlling for demographics, comorbidity score, and number of medications (incidence rate ratio = 1.13, p = .033). Adjusted total HCCs were 9% lower for VS (US$28,054 vs US$30,823, p = .045). In the unadjusted analysis, VS had greater emergency department (ED) utilization (45% vs 35%, p < .002). In the VS group, the mean (standard deviation [SD]) number of days from manufacturer switch to first outpatient visit was 23.8 (33.6), and the number of days (SD) to first TDM event was 43.6 (56.2). LIMITATIONS: Study limitations include the lack of availability of many transplant-specific variables within the Humana database, potential errors/omissions in claims coding, and restriction of cross-sectional data examination to a 1-year period. CONCLUSIONS: VS patients had greater TDM and lower total HCCs. Further research is warranted to understand the drivers of ED use among the VS group, and to determine factors associated with delayed TDM after regimen modification. Opportunities may exist to improve the quality of care for patients receiving immunosuppressant treatment with tacrolimus.

Bioavailability and costs of once-daily and twice-daily tacrolimus formulations in de novo kidney transplantation.

The use of once-daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once-daily tacrolimus (LCPT, Envarsus) and once-daily tacrolimus extended-release formulation (ER-Tac, Advagraf) compared with twice-daily immediate-release tacrolimus (IR-Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus-based immunosuppression within 2 clinical trials were included in a single-center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration-dose (C/D) ratio over 12 months. Intrapatient variability in trough levels and C/D ratios after 3 months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR-Tac, and 36 with ER-Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195-8.892€) for LCPT, 9.813€ (IQR 7.630-16.832€) for IR-Tac, and 9.838€ (IQR 7.503- 13.541€) for ER-Tac (Kruskal-Wallis test, P = .003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT.

Large-Scale Variability of Inpatient Tacrolimus Therapeutic Drug Monitoring at an Academic Transplant Center: A Retrospective Study.

BACKGROUND: Inpatient tacrolimus therapeutic drug monitoring (TDM) lacks standardized guidelines. In this study, the authors analyzed variability in the preanalytical phase of the inpatient tacrolimus TDM process at their institution. METHODS: Patients receiving tacrolimus (twice-daily formulation) and tacrolimus laboratory analysis were included in the study. Times of tacrolimus administration and laboratory study collection were extracted, and time distribution plots for each step in the inpatient TDM process were generated. RESULTS: Trough levels were drawn appropriately in 25.9% of the cases. Timing between doses was consistent, with 91.9% of the following dose administrations occurring 12 ± 2 hours after the previous dose. Only 38.1% of the drug administrations occurred within 1 hour of laboratory study collection. Tacrolimus-related patient safety events were reported at a rate of 1.9 events per month while incorrect timing of TDM sample collection occurred approximately 200 times per month. Root cause analysis identified a TDM process marked by a lack of communication and coordination of drug administration and TDM sample collection. Extrapolating findings nationwide, we estimate $22 million in laboratory costs wasted annually. CONCLUSIONS: Based on this large single-center study, the authors concluded that the inpatient TDM process is prone to timing errors, thus is financially wasteful, and at its worst harmful to patients due to clinical decisions being made on the basis of unreliable data. Further work is needed on systems solutions to better align the laboratory study collection and drug administration processes.

Economic assessment of actual prescription of drugs for treatment of atopic dermatitis: Differences between dermatology and pediatrics in large-scale receipt data.

Using large-scale receipt data, we analyzed the differences in the prescription of drugs and their costs between dermatology and pediatrics in the treatment of atopic dermatitis (AD) in children. Between August 2010 and July 2011, 50 706 patients were diagnosed as having AD, and the data of 21 075 (15 257 dermatology, 5818 pediatric) patients aged 0-14 years were included in this study. The use of classes I (strongest), II (very strong), and III (strong) topical corticosteroids and tacrolimus was significantly higher in dermatology than in pediatrics (class I, 2.88% vs 0.76%; class II, 27.68% vs 8.32%; class III, 52.53% vs 39.88%; tacrolimus, 5.05% vs 2.82%; all P < 0.05). Although total drug costs were higher in dermatology than in pediatrics, mean drug costs per person were significantly higher in pediatrics. Moisturizers and protective agents had the highest cost (~ ¥690 million). The introduction rate of generic drugs was low at 8.3% among classes I-V. The introduction rate of moisturizers and protective agents, for which costs were the highest, was approximately 9%. The prescription of generic classes II-V topical corticosteroids and moisturizers and protective agents was also significantly higher in dermatology than in pediatrics (P < 0.05). Among patients younger than 2 years, 4405 received drugs for AD; classes I and II topical corticosteroids and tacrolimus (against the guidelines) were administrated in 35 (0.8%), 474 (10.8%) and 29 patients (0.7%), respectively. The introduction of generic drugs is still low, and the use of generic moisturizers and protective agents should be addressed further.

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients.

OBJECTIVES: After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients. MATERIALS AND METHODS: This observational study inclu-ded 44 liver transplant patients (median age of 59 y; 63.6% men; median delay after transplant of 72.5 mo). Conversion was based on a 1:0.70 proportion. RESULTS: Mean dose of tacrolimus was 2.65 ± 1.24 mg/day before conversion and 2.09 ± 1.68 mg/day after conversion (P < .05), with ratio of 1:0.79. Mean serum tacrolimus trough level increased after conversion (4.92 ± 1.65 vs 5.60 ± 2.89 ng/mL; P < .05), with ratio of 1:1.14. Six months after conversion, mean dose of tacrolimus was 1.65 ± 0.93 mg/day (ratio of 1:0.62) and mean serum tacrolimus trough level was 4.82 ± 1.85 ng/mL, similar to the initial level before conversion. At the end of follow-up, 2 patients had returned to once-daily prolonged-release tacrolimus because of adverse effects (allergy, digestive trouble), which resolved thereafter. The mean cost of tacrolimus therapy was 5.54 ± 2.29 Euros/patient/day before conversion and 4.11 ± 2.32 Euros/patient/day after conversion (P < .05). CONCLUSIONS: Conversion from prolonged-release to extended-release tacrolimus in stable liver transplant patients is safe and cost-effective; however, initially, dose adaptations and careful monitoring are required.

Wuzhi Tablet (Schisandra sphenanthera Extract) is a Promising Tacrolimus-Sparing Agent for Renal Transplant Recipients Who are CYP3A5 Expressers: a Two-Phase Prospective Study.

Tacrolimus is a potent but expensive first-line immunosuppressant, thus solutions to reduce tacrolimus consumption while maintain therapeutic level are in urgent need. A two-phase prospective study was conducted to assess the efficacy of an ethanolic extraction preparation of Schisandra sphenanthera (Wuzhi tablet) as a tacrolimus-sparing agent in renal transplant recipients who were high-dose tacrolimus consumers (CYP3A5*1 allele carriers, CYP3A5 expressers). A total of 12 patients were included in the Part I study. After co-administration of Wuzhi tablet, the average individual increment (%) in dose-adjusted C0, Cmax and AUC0-12 hour of tacrolimus were 198.8% (95% CI 149.2, 248.3), 111.0% (95% CI 63.4, 158.6) and 126.1% (95% CI 89.4, 162.8), respectively (P < 0.01), while the average individual reduction (%) in tacrolimus daily dose was 40.9% (95% CI 25.2, 56.6) (P < 0.01). Subsequently, 32 patients were enrolled in a prospective, randomized, controlled study and randomly assigned to receive tacrolimus by CYP3A5 genotype plus Wuzhi tablet co-administration guided dosing (study group) or standard dosing (control group). Besides less tacrolimus dose requirement (P < 0.01), a more accurate tacrolimus initial dose characterized by lower incidence of out-of-range C0 after initial dose (P < 0.01) and fewer dose changes (P < 0.01) was found in the study group. Moreover, no significant differences in acute rejection rate and serum creatinine levels were observed between two groups. Our results show that CYP3A5 genotype plus Wuzhi tablet co-administration guided tacrolimus dosing is a promising therapy for CYP3A5 expressers in the early post-transplant stage, while further study with a larger sample size is required to prove these findings.

Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model.

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.

Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation.

BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [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), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES: Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS: Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS: Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS: The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS: TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014013544. FUNDING: The National Institute for Health Research HTA programme.

A cost-utility analysis of prolonged-release tacrolimus relative to immediate-release tacrolimus and ciclosporin in liver transplant recipients in the UK.

BACKGROUND: Calcineurin inhibitors (CNIs) represent the cornerstone of immunosuppressive therapy after liver transplantation. A recent network meta-analysis (NMA) evaluated the relative efficacy of CNIs ciclosporin, prolonged-release (PR) tacrolimus, and immediate-release (IR) tacrolimus in adult liver transplant recipients based on randomized and large observational trials published since 2000. Based on the NMA findings, the present study evaluated the cost-utility of PR tacrolimus relative to ciclosporin or IR tacrolimus in liver transplant recipients in the UK. METHODS: A Markov model was developed to evaluate the cost-utility of immunosuppressive regimens in liver transplant recipients, capturing costs associated with immunosuppression, retransplantation, acute rejection (AR), and cytomegalovirus infection. Mortality, graft loss, and AR odds ratios were derived from the NMA. Costs were taken from the British National Formulary and the NHS National Tariff and expressed in 2016 pounds sterling. Future costs and effects were discounted at 3.5% annually. RESULTS: Over 25 years, PR tacrolimus resulted in increased life expectancy and quality-adjusted life expectancy (QALE) relative to IR tacrolimus and ciclosporin. Relative to ciclosporin, QALE increased by 1.17 quality-adjusted life years (QALYs) with PR tacrolimus while costs increased by GBP £4645, yielding an incremental cost-effectiveness ratio (ICER) of £3962 per QALY gained. Relative to IR tacrolimus, QALE increased by 0.78 QALYs and costs by £1474, resulting in an ICER of £1889 per QALY gained. Sensitivity analysis showed the analysis to be most sensitive to dosing assumptions. CONCLUSIONS: Based on a UK-specific analysis of the projected cost-utility of PR tacrolimus relative to IR tacrolimus and ciclosporin, PR tacrolimus was cost-effective, improving life expectancy and QALE relative to both IR tacrolimus and ciclosporin, yielding ICERs below £20 000 per QALY gained. The main limitations of the study were data source heterogeneity and omitting the economic and clinical effects of treating aspects of recurrent liver disease.

Cost-effectiveness of everolimus plus reduced tacrolimus in de novo liver-recipients in the Italian setting.

INTRODUCTION: Long-term exposure to calcineurin inhibitor-based immunosuppressant (IS) therapy in liver transplant (LT) recipients is associated with renal complications. In the randomized trial H2304, everolimus + reduced-dose tacrolimus (EVR + rTAC) demonstrated equivalent efficacy and superior renal function compared to standard-dose tacrolimus. METHODS: To evaluate the cost-effectiveness of EVR + rTAC vs TAC, in de novo LT patients, a Markov model simulating both liver and kidney function was developed and estimated the long-term outcomes of IS following LT. The analysis used the Italian healthcare payer perspective. RESULTS: Patients treated with EVR + rTAC gained on average 1.92 years and 1.62 quality-adjusted life years (QALYs). The incremental cost-effectiveness ratios (ICER) were €35,851 and €42,567 for LY gained and QALY gained, respectively. For the hepatitis-c sub-population, the ICERs decreased to €22,519 and €30,658, respectively. CONCLUSION: EVR + rTAC improves survival and quality-of-life and is a cost-effective alternative to calcineurin-inhibitor monotherapy for patients requiring LT.

Multinational Evaluation of Mycophenolic Acid, Tacrolimus, Cyclosporin, Sirolimus, and Everolimus Utilization.

BACKGROUND: Increasing immunosuppressant utilization and expenditure is a worldwide challenge as more people successfully live with transplanted organs. Our aims were to characterize utilization of mycophenolate, tacrolimus, cyclosporin, sirolimus, and everolimus in Australian transplant recipients from 2007 to 2013; to identify specific patterns of usage; and to compare Australian utilization with Norwegian, Danish, Swedish, and the Netherlands use. MATERIAL AND METHODS: Australian utilization and expenditure data were captured through national Pharmaceutical Benefits Scheme and Highly Specialized Drug administrative databases. Norwegian, Danish, Swedish, and the Netherlands utilization were retrieved from their healthcare databases. Utilization was compared as defined daily dose per 1000 population per day (DDD/1000 population/day). Data on kidney transplant recipients, the predominant patient group prescribed these medicines, were obtained from international transplant registries. RESULTS: From 2007-2013 Australian utilization of mycophenolic acid, tacrolimus and everolimus increased 2.7-fold, 2.2-fold, and 2.3-fold, respectively. Use of cyclosporin and sirolimus decreased 20% and 30%, respectively. Australian utilization was significantly lower than European utilization (2013) but was increasing at a faster rate. Total Australian expenditure increased approximately AUD$30 million over the study period to almost AUD$100 million in 2013. Kidney transplantation rates increased across each country over this time, with Australia having the lowest rate. CONCLUSIONS: Immunosuppressant usage and subsequent expenditure are rising in Australia and Northern Europe. With increased numbers of people living with transplants, and the observed growth potential predicted from Northern European data, this class of medicines can be expected to continue consuming an increasing share of Australian pharmaceutical expenditure into the future.

Sirolimus Versus Tacrolimus as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation.

Sirolimus and tacrolimus 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 sirolimus 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 (AR), 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 QALYs gained and incremental cost-effectiveness. Altogether, 1189 patients from 8 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of AR and patient withdrawn. Nevertheless, tacrolimus increased the risk of infection. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events after renal transplant. Tacrolimus is an effective and safe immunosuppressive agent, and it may be more cost-effective than cyclosporine for the primary prevention of AR in renal transplant recipients. However, it should be noted that such superiority was reversal when the cost of sirolimus and tacrolimus changed.

Tacrolimus Versus Cyclosporine as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation.

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.

Generics: are all immunosuppression agents created equally?

BACKGROUND: The Affordable Care Act initiated innumerable cost-containment measures, including promoting generic conversion from brand medications and directing the Food and Drug Administration to decrease requirements for generic approvals. Despite this mandate, few data existed on generic conversion of immunosuppressant medications with narrow therapeutic troughs. METHODS: A retrospective analysis of our initial experience with generic tacrolimus (n = 39) was performed using a control cohort from our renal transplant database. A rejection and cost analysis was performed using a consecutive 2-year prior cohort (n = 159) as a control to determine the effect of generic conversion on tacrolimus a narrow therapeutic index immunosuppressant medication. RESULTS: During the first year after transplantation, the generic group had a greater drug variability (20% ± change in trough levels) that required more dosage adjustments (5.42 vs 3.59 drug dosage changes; P = .038) to obtain a stable dose, required increased number of intravenous magnesium infusions (4.95 vs 1.68 infusions; P = .001), and incurred a greater incidence of rejection (23.1% vs 10.2%; P = .024). A yearly institutional cost was evaluated against a negotiated $18,000/yearly central pharmacy cost savings compared with a $652,862 institutional cost to treat unanticipated rejections. CONCLUSION: Programmatic conversion from brand to generic tacrolimus resulted in increased drug variability, a greater incidence of magnesium wasting, and more episodes of rejection, leading to increases in institutional costs of care. This government-driven attempt at cost containment may be applicable to noncritical medications such as antibiotics and antihypertensives, but this policy should be reconsidered for narrow therapeutic index medications, such as tacrolimus and other immunosuppressant medications.