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Prediction of mizoribine pharmacokinetic parameters by serum creatinine in renal transplant recipients.
European Journal of Clinical Pharmacology 2019 March
PURPOSE: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
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