Single daily high-dose mizoribine therapy for children with steroid-dependent nephrotic syndrome prior to cyclosporine administration

Abstract

Although cyclosporine (CsA) therapy is effective in the management of children with steroid-dependent nephrotic syndrome (SDNS), a recent study has revealed that the use of CsA itself was a significant predictor of NS relapse in adulthood. The efficacy of single daily high-dose mizoribine (MZR) therapy was assessed in 10 children with SDNS (mean age, 6.2 years) who had never been treated with CsA previously. MZR was started at 5 mg/kg, administered as a single daily dose after breakfast, and the dose was adjusted to achieve 2-h post-dose MZR levels (C2) of approximately 3 μg/ml. In 9 of the 10 patients, treatment with a single daily dose of MZR (mean dose, 8.4 mg/kg/day) over a period of 22 months (median) resulted in significant reduction of the mean prednisolone dose from 0.39 to 0.15 mg/kg/day and the median 12-month relapse rate from 3.0 to 0.4 episodes/12 months. Although cyclophosphamide was initiated in one patient because of treatment failure, none of the 10 patients required treatment with CsA during the observation period (median, 33 months). These data indicate that single daily high-dose MZR therapy is possibly useful in treating children with SDNS and that it may also eliminate the need for CsA in some patients.

Cyclophosphamide followed by mizoribine as maintenance therapy against refractory steroid-dependent nephrotic syndrome

“…Its efficacy in preventing relapse is not as potent as CPA or cyclosporine (CsA). However, high-dose MZR is broadly used for SDNS and FRNS in Japan because of its safety for long-term use, which is similar to that reported for MMF in the USA [7,8]. In our study, we treated nine patients with SDNS with 4.4-9.4 mg/kg of MZR, once-daily dosing, beginning on the day following discontinuation of CPA, and observed the patients for 2 years.…”

Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial

“…In our trial and that of Bagga et al [14], SDNS children received MMF after one course of cyclophosphamide had failed to improve steroid dependency, as commonly done in recent decades. Interestingly, mizoribine, a purine-metabolism inhibitor that mimics MMF, has been shown to induce a significant reduction of prednisolone dose and relapse rate in nine of ten children with SDNS who had received neither cyclophosphamide nor cyclosporine previously [42]. Therefore, cyclophosphamide, because of its adverse effects and relatively low efficacy in SDNS [34][35][36], should now rather be positioned after MMF and cyclosporine, as proposed [38,39].…”

Clinical practice guideline for pediatric idiopathic nephrotic syndrome 2013: medical therapy

“…Multiple studies of high-dose mizoribine therapy for frequently-relapsing and steroid-dependent nephrotic syndrome were then reported, including those investigating the efficacy and safety of mizoribine at 10 mg/kg/day (maximum 500 mg) twice a week [71], 6 mg/kg/day (maximum 300 mg) twice a week [72], a mean of 14.3 mg/kg/day twice a week [73], a mean of 10.1 mg/kg/day daily [74], and a mean of 8.4 mg/kg/day daily [75]. A cohort study comparing the standard dose (4-6 mg/kg/day) and highdose (7-10 mg/kg/day) of mizoribine demonstrated superior efficacy of high-dose therapy, with a significant decrease in the number of relapses in patients with a peak blood mizoribine concentration of 3.0 lg/mL or higher [76].…”