Prediction of mizoribine pharmacokinetic parameters by serum creatinine in renal transplant recipients
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Mizoribine (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.
A total of 40 renal transplant recipients participated in this prospective study and were administered MZR orally twice daily in the range of 1.1–8.9 mg kg−1 day−1. Steady-state concentrations of MZR were detected before (0 h) and 0.5, 1, 2, 3, 4, 5, 6, 8, and 12 h after administration by high-performance liquid chromatography method. Another 38 patients with newly detected trough concentration (C0) were enrolled to validate the obtained C0 predictive equation.
Significant inter-individual differences in MZR PK parameters were observed. Patients with decreasing creatinine clearance rate (CCr) had significantly decreased terminal elimination rate constant (kel) and apparent total body clearance (Cl/F), while other PK parameters including apparent terminal half-life (t1/2), peak time (Tmax), peak concentration (Cmax), area under the curve (AUC0-12h), apparent volume of distribution (V/F), and mean residence time (MRT) were significantly increased. Correlation coefficients between AUC0-12h and C0/Cmax were 0.894 and 0.916, respectively (both p < 0.001). A serum creatinine (SCr)-based predictive C0 equation [C0 = (2.160 × SCr − 54.473) × Dose] was established and validated by C0 from another 38 patients. Besides, significant linear correlations between kel/t1/2 and CCr were also found (r2 = 0.668 and 0.484, respectively), and equations predicting kel/t1/2 were also obtained (kel = 0.015 + 0.002 × CCr, t1/2 = 13.601 − 0.139 × CCr).
Renal function plays as an essential factor that contributes to great inter-individual MZR PK variation. Both C0 and Cmax are suitable for evaluating MZR exposure in the body. SCr could be applied to predict C0 and t1/2 of MZR.
KeywordsMizoribine Renal transplantation Pharmacokinetics Immunosuppression
Concept and design: Changxi Wang, Jie Chen
Acquisition of data: Longshan Liu, Qian Fu
Drug concentration determination: Jingjing Wu
Analysis and interpretation of the data: Pan Chen, Xuan Xu, Jingjie Li
Drafting of the article: Xuan Xu, Pan Chen
Critical review: All authors
This study was financially supported by the National Natural Science Foundation of China (Grant: 81503156, 81601347), Natural Science Foundation of Guangdong Province (No. 2014A030310096), and Public Welfare Research and Capacity Building Fund of Guangdong (No. 2016A020218006).
Compliance with ethical standards
This study was approved by the ethics committee of the First Affiliated Hospital of Sun Yat-sen University (approved no: 2015118) and informed consent was obtained from each enrolled patient
Conflict of interest
The authors declare that they have no conflict of interest.
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