Mizoribine Versus Mycophenolate Mofetil in Combination Therapy With Tacrolimus for De Novo Kidney Transplantation: Evaluation of Efficacy and Safety

doi:10.1016/j.transproceed.2012.12.028

Transplantation Proceedings

Volume 45, Issue 4, May 2013, Pages 1481-1486

https://doi.org/10.1016/j.transproceed.2012.12.028 Get rights and content

Abstract

The present study compared the efficacy and safety of mizoribine (MZR) with mycophenolate mofetil (MMF) in kidney transplantation. This multicenter, randomized clinical trial. Employed doses of study drug tailored to the immunosuppressive need. The primary efficacy outcome was the incidence of biopsy-proven acute rejection episodes (BPAR). The safety of the study drug was assessed using the incidences of adverse events, drug discontinuations, and abnormal laboratory results. The 7 (6.4%) BPARs above grade II were observed in the MZR group noninferior to the 2 (1.8%) in the MMF group (95% confidence interval, −0.007–0.097 > noninferiority limit [−0.2]). BPAR was significantly decreased in the MZR group after the dose change (17/41 [41.4%] vs 8/69 [11.6%]; P < .0001) and the incidence of BPAR was similar between the MZR and MMF groups after the dose change (P = .592). The uric acid level was significantly elevated in the MZR group (P = .002). In conclusion, the efficacy and safety of MZR were similar and statistically noninferior to MMF in combination therapy with tacrolimus.

Section snippets

Patients and Methods

This 26-week, multicenter, open-label, prospective, and randomized clinical trial included end-stage renal failure patients undergoing de novo living or deceased donor kidney transplantation at 9 centers in South Korea between July 2008 and January 2011. Among 223 screened patients, 4 were excluded due to screening failure, including 2 surgery cancellations, 1 delayed surgery, and 1 protocol violation before study drug administration (Fig 1).

The MZR group received generic tacrolimus (TacroBell)

Patient Demographics

The ITT set analysis included 70 (63.6%) male and 40 (36.4%) female patients of mean age 44.6 ± 10.9 years in the MZR group vs 64 (58.7%) male and 45 (41.3%) female subjects of mean age of 44.2 ± 11.1 years in the MMF group. No significant differences were observed in patient demographics (Table 1).

Tacrolimus Trough Level and Change in Study Drug Dose

The tacrolimus trough levels were within the target range during the entire study period. Before the maximal permissible dose change, 17 (31.4%) BPARs and 4 (9.7%) BPARs were observed in the MZR

Discussion

We have previously reported the efficacy and safety of TacroBell, a generic tacrolimus formulation.8, 9 An acute rejection rate of 10.6% was observed among renal transplant patients treated with TacroBell.⁹ The acute rejection rate for MZR and MMF in combination with TacroBell was 13.7% in the current study; episodes greater than Banff 07 criteria grade II occurred among 4.1% of the total study population. These rates are comparable to the results of previous studies of Prograf.10, 11 Our

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Cited by (8)

Long-term Survival Analysis of Kidney Transplant Recipients Receiving Mizoribine as a Maintenance Immunosuppressant: A Single-Center Study
2019, Transplantation Proceedings
Citation Excerpt :
In Korea, there was only 1 report comparing MZR’s efficacy and safety with MMF. However, the short study period of 26 weeks limited the information that could be obtained on long-term use of MZR [9]. For kidney transplant recipients administered MZR, in 1999 Tanabe et al reported overall survival rates of 98% at 1 year, 93% at 5 years, and 88% at 9 years along with graft survival rates of 98% at 1 year, 73% at 5 years, and 58% at 9 years [10].
Mizoribine (MZR) has been developed as an immunosuppressant and is widely used in Asia. However, most studies on MZR have been performed in Japan, and there remains a lack of reports on long-term use in other countries. The purpose of this study is to evaluate the efficacy and safety of MZR’s use in Korean kidney transplant recipients by observing their clinical courses and analyzing their long-term patent and graft survival rates.
We studied 129 subjects who had received MZR as a maintenance immunosuppressant since January 2000. Our analysis was based on the patients’ medical records from January 2000 to December 2017.
The overall survival rates of the kidney transplant recipients were 100% at 1 year, 99.1% at 5 years, 96.8% at 10 years, and 92.5% at 15 years. The graft survival rates were 100% at 1 year, 98.3% at 5 years, 93.2% at 10 years, and 82.2% at 15 years. There were differences in the recipient survival and graft survival rates according to the kidney donor and the use of renal replace therapy before transplant. There were no differences in the survival rates according to the MZR dose, the type of underlying disease, or other clinical factors.
The use of low doses of MZR as a maintenance immunosuppressant could be an effective means of ensuring relatively good long-term patient and graft survival rates in cases of kidney transplant.
Comparative efficacy and safety of mizoribine with mycophenolate mofetil for Asian renal transplantation-A meta-analysis
2014, Clinical Biochemistry
Mizoribine (MZR) with its high safety and low cost has been widely used in Asia. It has been questioned whether high or low dose of MZR could obtain the efficacy and safety similar to mycophenolate mofetil (MMF) following renal transplantation. This meta-analysis was done to compare the efficacy and safety of high- or low-dose MZR with MMF for immunosuppressive therapy in renal transplantation.
Available data comparing MZR with MMF in renal transplant recipients were searched. Subgroup analysis was conducted according to the administration dosage of MZR. Trials were pooled using Meta-analysis software and confidence intervals were set at 95%.
Altogether 1149 Asian patients from 7 RCTs and 9 cohort studies were included. The efficacy of different MZR doses put on par with MMF, but the safety was better than MMF. Specifically, recipients taking MZR favor significantly fewer episodes of leucocytopenia [RR 0.40 (0.26, 0.60)], gastrointestinal disorder [RR 0.54 (0.40, 0.73)], CMV infection [RR 0.47 (0.34, 0.64)] and more favorable outcome of hepatic dysfunction, although the difference failed to reach a statistical significance [RR 0.67 (0.44, 1.00)]. Unfortunately, hyperuricemia was significantly obvious in MZR group [RR 1.96 (1.47, 2.61)].
MZR is an effective and safe immunosuppressive agent and high-dose MZR can be recommended as an alternative to MMF following adult renal transplantation in Asia, but hyperuricemia and liver damage should be closely monitored during the medication period.
The Efficacy and Safety of Mizoribine versus Mycophenolate Mofetil for the Treatment of Renal Transplantation: A Systematic Review and Meta-Analysis
2022, Computational Intelligence and Neuroscience
IMPDH inhibitors for antitumor therapy in tuberous sclerosis complex
2020, JCI Insight
Efficacy and safety of a quadruple regimen compared with triple regimens in patients with Mycophenolic acid-related gastrointestinal complications after renal transplantation: A short-term single-center study
2020, Annals of Transplantation
Efficacy and Safety of a Quadruple Regimen in Patients with Gastrointestinal Complications after Renal Transplantation
2019, SSRN

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: This study was supported by The Chong Kun Dang Pharmaceutical Corp. Seoul, Korea.

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Renal transplantationImmunosuppressionMizoribine Versus Mycophenolate Mofetil in Combination Therapy With Tacrolimus for De Novo Kidney Transplantation: Evaluation of Efficacy and Safety

Abstract

Section snippets

Patients and Methods

Patient Demographics

Tacrolimus Trough Level and Change in Study Drug Dose

Discussion

Transplant Proc

Am J Transplant

Clin Ther

Transplant Proc

Transplant Proc

Transplant Proc

Transplant Proc

Renal transplantation
Immunosuppression
Mizoribine Versus Mycophenolate Mofetil in Combination Therapy With Tacrolimus for De Novo Kidney Transplantation: Evaluation of Efficacy and Safety