Mizoribine requires individual dosing due to variation of bioavailability

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Abstract

Background:

Mizoribine (MZR) is an immunosuppressant used for the treatment of glomerular diseases, but there are few reports on the pharmacokinetics of MZR in children.

Methods:

First, we performed a pharmacokinetic study on nine childhood-onset glomerular disease patients. The MZR dosages ranged from 1.8 to 14.5 mg/kg/dose. Pharmacokinetic parameters were analyzed using 38 MZR concentration-time curves. Second, nine patients who were newly treated with MZR were enrolled to validate the findings obtained from prior investigation.

Results:

In the prior study, peak serum MZR concentration (Cmax) was dose-dependent in each patient. Although proportionality between dosage and Cmax was observed in each patient, the regression coefficient was in a wide range from 0.075 to 1.04 and was specific to each patient. This variability was likely caused by individual variation of bioavailability. When the optimal time-point to monitor Cmax was investigated, the time-to-reach peak serum MZR concentration (Tmax) was similar among all the patients, which was from 2.5 to 3.5 h after administration of MZR. Tmax was most frequently observed at 3 h and the serum MZR concentration ratio relative to Cmax at 3 h was also highest (0.93 ± 0.07). In the following study, it was validated that monitoring C3 is reproducible and reliable after adjusting the dosage of MZR to obtain target serum concentration.

Conclusion:

Individual dosing is required to optimize Cmax in childhood-onset glomerular disease patients. The safe dosage of MZR for each patient could be predicted by evaluating the serum MZR concentration 3 h after administration.

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