Revival of effective and safe high‐dose mizoribine for the kidney transplantation*

Abstract

We investigated whether high-dose Mizoribine (MIZ: a water-soluble anti-metabolite), 4-6 mg/kg/d was as effective and safe as mycophenolate mofetil (MMF) for patients after kidney transplantation. Between January 2001 and December 2005, 36 recipients at a stable phase more than one month passed after transplantation underwent conversion from MMF to MIZ, two from Azathioprine to MIZ, and two cases on MIZ from the beginning. There were 24-male and 16-female patients whose average age was 43.3 yr old and average weight was 54.0 kg. The types of transplantations were living donor renal transplantation 25, cadaveric renal transplantation 11, and simultaneous pancreas-kidney transplantation four examples. Of these, 33 patients were on Tacrolimus-based triple regimen and seven patients on Cyclosporine A base. The drugs used together with MIZ were basically the same as those before conversion. The reasons for conversion to MIZ were infection in 18 cases (45.0%), bone marrow suppression in nine cases (22.5%) and diarrhea in eight cases (20.0%), and post-transplant lymphoproliferative disorder in one case (2.5%). We initiated 4-6 mg/kg/d of MIZ divided twice a day depending on the serum creatinine (sCr) value of each patient. There was no big difference in the sCr value before and after MIZ administration in each individual patient, 1.79 +/- 1.37 and 1.65 +/- 1.30 mg/dL, respectively. A 12 h pharmaco-kinetic study of MIZ revealed that a peak value reached 2.87 microg/mL on average at three h (C3) followed by a slow decrease afterward. Acute rejection occurred in two cases and adverse effects were seen in five cases. The results of analysis of 349 points divided into three groups by renal function were as follows; poor renal function Group A revealed a trough level of 2.21 +/- 0.99 microg/mL and dosage 2.20 +/- 1.06 mg/kg, good renal function Group B had a trough level of 1.06 +/- 0.82 microg/mL and dosage 4.40 +/- 1.72 mg/kg, and excellent function Group C had a trough level of 0.92 +/- 0.55 microg/mL and dosage of 4.36 +/- 1.08 mg/kg. High-dose MIZ 4-6 mg/kg/d is an anti-metabolite having an equivalent immunosuppressive effect, fewer serious adverse events and good cost-effectiveness as MMF even for patients with prolonged hemodialysis period and declined digestive function in Japan.

Population pharmacokinetics of mizoribine in adult recipients of renal transplantation

“…Sugitani et al [15] evaluated the blood concentrations and clinical efficacy of mizoribine in 36 renal transplantation patients who were shifted from mycophenolate mofetil to mizoribine. The immunosuppressive effect of mizoribine was observed over a long period without severe adverse reactions in patients whose trough concentrations of mizoribine were to be kept higher than 1 lg/mL [15]. On the other hand, Sonda et al [16] investigated the blood concentrations and adverse reactions of mizoribine in 46 renal transplantation patients.…”

“…The clinical efficacy (adverse reactions) of mizoribine is considered to be correlated with the blood concentration of the drug; however, there are few reports about TDM-based dosage regimens of mizoribine in patients with renal transplantation [15,16]. Sugitani et al [15] evaluated the blood concentrations and clinical efficacy of mizoribine in 36 renal transplantation patients who were shifted from mycophenolate mofetil to mizoribine.…”

Improvement in Severe Mycophenolic Acid-associated Gastrointestinal Symptoms after Changing Enteric-coated Mycophenolate Sodium to Mizoribine in Renal Transplant Recipients: Two Case Reports

“…Although it has also been released in South Korea and China, it has not seen wide acceptance throughout the world due to its less immunosuppressive potency, despite its fewer adverse events (17). Recently, a meta-analysis compared the efficacy and safety of mizoribine with mycophenolate mofetil as immunosuppressive therapy in Asian transplant recipients.…”

Impact of Concentrative Nucleoside Transporter 1 Gene Polymorphism on Oral Bioavailability of Mizoribine in Stable Kidney Transplant Recipients

“…Mizoribine is an immunosuppressive anti‐metabolite having a selective inhibition of inosine monophosphate dehydrogenase as mycophenolate [21]. Sonda et al.…”