Background: Mizoribine (MZ) has been reported in many countries as an effective immunosuppressant with less myelosuppressive effect than mycophenolate mofetil (MMF). The aim of this present study is to assess the efficacy and safety of mizoribine as an alternative immunosuppressant for renal transplant recipients with MMF-sensitive leucopenia, and to investigate its therapeutic exposure as well.

Patients and Methods: Nineteen MMF-sensitive leucopenia patients who underwent renal transplantation between August 2006 and November 2007 were prescribed mizoribine to replace mycophenolate mofetil. The subjects were comprised of 14 male and 5 female cases with an average age of 42 ± 10.6 years. The concomitant immunosuppressants were tacrolimus plus steroids in 11 patients, and cyclosporine plus steroids in 8 patients. All the patients presented stable graft function. Mizoribine was administered by 100 mg per day (twice daily), and pharmacokinetic monitoring was performed 14 days after MZ initiation. Peripheral vein blood samples were harvested right before MZ administration (0 h) and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10 and 12 h after the administration. MZ plasma concentrations were measured by high performance liquid chromatogram (HPLC). MZ dose was then adjusted when necessary according to its concentration and clinical features. Hemogram, renal and hepatic function were routinely measured during the follow-up.

Results: Patients were followed up for 3 to 18 months. White blood count (WBC) recovered in all the patients from 3.0 ± 0.4×109/L to 6.4 ± 0.8×109/L (P＜0.01). Renal graft function maintained stable and no acute rejection observed. Serum creatinine (sCr) was 119 ± 27.4 μmol/L before MZ initiation, and maintained at 114 ± 30.5μmol/L by the latest examination (P＞0.05). Blood uric acid increased in 10 patients and seven developed hyperuricacidemia with a level of 512 ± 58.9 mmol/L. However, normal blood uric acid level was achieved in all the seven patients when applying Allopurinol.

As pharmacokinetic features of Mizoribine in these patients, its trough level (C0) was 0.31 ± 0.16μg/mL, Cmax 1.21 ± 0.55 μg/mL, Tmax 3.5 ± 1.2 h, and AUC0-12 h was 8.4 ± 3.6 (μg/mL)•h. MZ dose was subtracted one half in one patient with high trough level and serum creatinine whose leucopenia was constant when using 100 mg per day. Meanwhile, MZ dose was increased to 150 mg per day in two patients with low C0 (0.09μg/mL) and AUC0-12 h [3.07 (μg/mL)•h].

Conclusion: Mizoribine is an alternative immunosuppressant for renal transplant patients with MMF-sensitive leucopenia except for inducing hyperuricacidemia. Dose adjustment according to its individual pharmacokinetics should be considered especially for recipients with low therapeutic exposure or with impaired graft function.