Population pharmacokinetics of mizoribine in pediatric recipients of renal transplantation

An immunosuppressive agent, mizoribine, is excreted predominantly in the urine. The aim of this study was to investigate the pharmacokinetic variability of mizoribine in pediatric recipients of renal transplantation. Pharmacokinetic data for population analysis were collected from 51 recipients (32 males and 19 females) treated with oral administration of mizoribine (0.83-5.56 mg/day/kg). The population pharmacokinetic parameters of mizoribine were estimated using a nonlinear mixed effects model program. The pharmacokinetics of mizoribine in pediatric recipients of renal transplantation was well described by a one-compartment model with first-order absorption. The mean value of the absorption lag time (ALAG) and absorption rate constant (K (A)) was estimated to be 0.363 h and 0.554 h(-1), respectively. Apparent volume of distribution (V/F) was modeled as a function of body weight (WT), and the mean value was estimated to be 1.03 center dot A WT L. Oral clearance (CL/F) was modeled as a function of creatinine clearance (CLcr), and the mean value was estimated to be 2.81 center dot A CLcr center dot A 60/1000 L/h. In addition, there was a positive correlation between CLcr-corrected CL/F and WT-corrected V/F in the pediatric recipients, indicating large interindividual variability in the bioavailability (F) of mizoribine. The present findings indicated that the rate of renal excretion and also the extent of intestinal absorption of mizoribine are responsible for the large interindividual pharmacokinetic variability of the drug.