Do Calcineurin Inhibitors Influence the Serum Concentrations of Mizoribine?

Abstract

Background, Objectives and Subjects: Mizoribine (MZR) is an antimetabolite that inhibits inosine-monophosphate dehydrogenase just like mycophenolate mofetil (MMF), and has been used for preventing rejection in cases of renal transplantation. It has been reported that the biokinetics of mycophenolic acid (MPA), which is the metabolically activated form of MMF, shows large variations among individuals, depending on the renal function, concomitant use of a calcineurin inhibitor (CNI), corticosteroid, etc. On the other hand, the biokinetics of mizoribine (MZR) is known to be influenced strongly by the renal function, but not by concomitant use of drugs, including CNIs. However, there are no reports referring to clinical investigations of the effect of CNIs on the biokinetics of MZR. Therefore, we conducted this study, based on population pharmacokinetic analysis (PPK), to determine whether concomitant use of CNIs (tacrolimus (Tac) or cyclosporine (CyA)) may exert any influence on the biokinetics of MZR, in living-donor renal transplant recipients administered a 4-drug immunosuppressive therapy regimen, including MZR 6 mg/kg/day. Results: The PPK analysis revealed that the correlation coefficients between the actual and estimated serum concentrations of MZR in the CyA group and Tac group were 0.992 and 0.988 respectively, indicative of a good correlation. The PPK parameters (ka, V/F and CL/F) in both groups were nearly identical, therefore, it was considered that concomitantly used CNIs were unlikely to have any significant influence on the biokinetics of MZR (absorption, distribution and excretion). Actually, the average value of the areas under the curve (AUCs) of MZR corrected by the creatinine clearance in the CyA group and Tac group were 9.24 ± 3.24 and 10.23 ± 3.46 (μg·hr/mL)/μg·mL/min, respectively, which confirmed that concomitant CNI use exerts little influence on the serum concentration of MZR. Conclusion: It was concluded that concomitant use of CNIs, e.g., Tac and CyA, may have no significant influence on the pharmacokinetics of MZR.