The Effect of Cyclosporine、Tacrolimus and Sirolimus on the Concentration of Mycophenolic Acid in Renal Transplant Recipients Taking Mycophenolate Mofetil

Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is used in combination with other immunosuppressants for the prevention of rejection after solid organ transplantation. MPA, the active metabolite of mycophenolate mofetil, acts by inhibiting the de novo pathway of purine synthesis. Several studies have demonstrated a relationship between mycophenolic acid exposure and the incidence of acute rejection(van Gelder
1999; Pillans 2001; Kiberd 2004). The exposure to mycophenolic acid was also significantly related to infections and hematological toxicity(Atcheson 2005).
In renal transplant recipients, MMF is currently administered at a dose of 1 to 2g daily without monitor of the drug level. The objectives of this study were to
compare the concentration of mycophenolic acid between patients receiving mycophenolate mofetil and either cyclosporine, tacrolimus or sirolimus and to
investigate the factors that influenced serum MPA level.
Methods:
This study recruited patients who received renal transplantation in National Taiwan University Hospital between Jan. 2000 and Jan. 2006 with stable post-transplantation renal function for more then 6 months. All patients were neither hepatitis B nor hepatitis C carrier. Patients were divided into 3 groups according to their immunosuppressant regimens, either cyclosporine
(n=7), tacrolimus (n=15) or sirolimus (without calcineurin inhibitor, n=24). Besides calcineurin inhibitor or sirolimus, all patients also received steroid and
0.5g to 1g of MMF twice daily by oral route. Patients who took both calcineurin inhibitor and sirolimus were not included in this study. Blood samples were collected from these patients for measurement of pre-dose (C0),
0.5 hour post-dose (C0.5) and 2 hour post-dose (C2) MPA concentration. Renal function and trough serum level of cyclosporine, tacrolimus or sirolimus of these patients were followed monthly for at least 6 months. Emit® 2000 Mycophenolic Acid Assay (Syva Company, Dade Behring Inc., Cupertino, CA, USA) was used to measure plasma MPA concentration. The MPA concentration and estimated AUC were compared among the 3 groups.
Results:
We collected data from 46 patients in total, 24 patients in sirolimus group, 15 in tacrolimus group and 7 in cyclosporine group. First of all, we wanted to know whether body weight or dosage of MMF would influence MPA
concentration in plasma. In this study, 0.5 hour post-dose MPA concentration was significantly correlated with the dosage of MMF (p=0.005, ANCOVA) but not the body weight (p=0.697, ANCOVA). Therefore, we used daily MMF dose-normalized MPA concentration for further comparison. The MMF dosenormalized trough MAP concentration and 2 hour post-dose MPA concentration were not significantly different among the three groups. The MMF dose-normalized 0.5 hour post-dose MPA concentration in the cyclosporine group (4+2.11mg/L) was significantly lower than that in the
sirolimus group (13.93+9 mg/L; P=0.004) or tacrolimus group (11.55+6.3 mg/L；P=0.034, multiple regression).
Conclusion:
We demonstrated that 0.5 hour post-dose MPA concentration was significantly correlated with the daily dosage of MMF but not the body weight. The MMF dose-normalized 0.5 hour post-dose MPA concentration in the cyclosporine group was significantly lower than that in the sirolimus group or
tacrolimus group.