Prediction of mizoribine pharmacokinetic parameters by serum creatinine in renal transplant recipients

PurposeMizoribine (MZR) is an immunosuppressive agent with extensive inter-individual differences in pharmacokinetics (PK). Here, we investigated the PK characteristics of MZR in renal transplant recipients and gave equations for prediction of some critical PK parameters.MethodsA total of 40 renal transplant recipients participated in this prospective study and were administered MZR orally twice daily in the range of 1.1-8.9mgkg(-1)day(-1). Steady-state concentrations of MZR were detected before (0h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12h after administration by high-performance liquid chromatography method. Another 38 patients with newly detected trough concentration (C-0) were enrolled to validate the obtained C-0 predictive equation.ResultsSignificant inter-individual differences in MZR PK parameters were observed. Patients with decreasing creatinine clearance rate (CCr) had significantly decreased terminal elimination rate constant (k(el)) and apparent total body clearance (Cl/F), while other PK parameters including apparent terminal half-life (t(1/2)), peak time (T-max), peak concentration (C-max), area under the curve (AUC(0-12h)), apparent volume of distribution (V/F), and mean residence time (MRT) were significantly increased. Correlation coefficients between AUC(0-12h) and C-0/C-max were 0.894 and 0.916, respectively (both p<0.001). A serum creatinine (SCr)-based predictive C-0 equation [C-0=(2.160xSCr-54.473)xDose] was established and validated by C-0 from another 38 patients. Besides, significant linear correlations between k(el)/t(1/2) and CCr were also found (r(2)=0.668 and 0.484, respectively), and equations predicting k(el)/t(1/2) were also obtained (k(el)=0.015+0.002xCCr, t(1/2)=13.601-0.139xCCr).ConclusionsRenal function plays as an essential factor that contributes to great inter-individual MZR PK variation. Both C-0 and C-max are suitable for evaluating MZR exposure in the body. SCr could be applied to predict C-0 and t(1/2) of MZR.