腎臟移植病患服用Mycophenolate Mofetil同時合併服用Cyclosporine、 Tacrolimus 或是 Sirolimus對於血清中Mycophenolic Acid藥物濃度的影響

Abstract

Mycophenolate mofetil (MMF) 是一種免疫抑制劑，經常和其他抗排斥藥物合併使用在接受器官移植的病患上，預防移植器官排斥反應的發生。 Mycophenolic acid (MPA)是病患服用MMF之後，經過代謝在人體內所產生具有活性的代謝產物。MPA 主要作用在抑制purine 合成的de novo pathway，藉此抑制淋巴球的分裂來達成抑制免疫反應的目的。 一些研究指出血液中MPA 的濃度和急性排斥的發生率有相關。 而血液中MPA的濃度同時也和感染的發生率以及藥物毒性有相關。 目前在臨床上，MMF的使用是根據病患可以忍受的劑量，給予病患 口服一天兩次、 一次0.5~1g的MMF，而沒有監測血液中藥物濃度。 因此，在合併其他抗排斥藥物使用的情況下，不知道血液中MPA的濃度是否會因為併用其他藥物而改變。本研究的目的在於比較服用不同免疫抑制劑，包括cyclosporine、 tacrolimus 或是sirolimus (沒有合併使用calcineurin inhibitor) 的腎臟移植病患，血液中MPA濃度的是否不同，以作為臨床上調整藥物劑量的參考。 本研究收集從2000年1月到2006年1月在台大醫院外科進行腎臟移 植，移植腎的功能穩定達六個月以上的病患。所有病患皆非B或C型肝炎的帶原者。根據服用的免疫抑制藥的種類將病患分為三組，包括cyclosporine 、 tacrolimus或是sirolimus三組。 除了上述藥物以外，病人服用的免疫抑制劑還包括口服類固醇以及每天兩次、每次0.5~1g的MMF。 從這些腎臟移植的病患採集服藥前、 服藥後半小時、 以及服藥後兩小時的血液並測量血清中MPA的濃度。 這些病患的腎臟功能、服藥前血液中cyclosporine、 tacrolimus或是sirolimus的藥物濃度皆定期每個月於門診追蹤六個月以上。血清中MPA濃度的測量是使用Emit® 2000Mycophenolic Acid Assay (Syva company, Dade Behring Inc., Cupertino, CA,USA)。 我們發現服用的MMF劑量明顯影響服用MMF後半小時血清中MPA 濃度(p=0.005, ANCOVA)，而相對之下體重對於服用MMF後半小時血清中MPA濃度較無相關(p=0.697, ANCOVA)。因此，之後的MPA濃度比較我們都使用MMF藥物每日劑量校正後服藥後MPA濃度(dose-normalized MPA concentration) 作比較。在已經收集的三組個案sirolimus，tacrolimus 以及cyclosporine 裡，cyclosporine 組的藥物劑量校正後服藥後半小時(C0.5h) MPA 濃度 (4+2.11 mg/L)明顯低於sirolimus 組(13.93+9 mg/L; P=0.004)以及tacrolimus 組(11.55+6.3 mg/L；P=0.034, multiple regression)。也就是在服用MMF的腎臟移植受贈者，如果同時服用cyclosporine會比同時服用tacrolimus或是sirolimus有較低的服藥後半小時MPA 濃度。

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.