在新腎臟移植病人Everolimus對Tacrolimus藥動學的影響：以Mycophenolate Mofetil作為對照組

Effect of Everolimus on Tacrolimus Pharmacokinetics in De Novo Renal Transplant Recipients: Using Mycophenolate Mofetil as a Control

張瑄玶(Hsuan-Ping Chang)

指導教授 ： 林慧玲 ； 蔡孟昆

國立臺灣大學/藥學專業學院/臨床藥學研究所/碩士(2015年)

https://doi.org/10.6342/NTU.2015.10322

摘要

簡介：
有關everolimus (EVL) 對tacrolimus (TAC) 藥品動態學 (簡稱藥動學) 影響的研究很少，且結果並不一致，而過去研究顯示mycophenolate mofetil (MMF) 對於TAC藥動學的影響很小，未達統計上差異，故本研究欲以MMF-TAC為對照組，探討EVL對TAC藥動學的影響。

方法：
本研究為一前瞻性、隨機分配、開放性試驗，納入初次接受腎臟移植且年齡在20-65歲的病人，排除條件包括：懷孕、再移植或多重器官移植、人類免疫缺乏病毒反應呈陽性、B型或C型肝炎帶原、胺基轉化酶數值在正常值上限的兩倍以上，以及有類風濕關節炎病史。病人納入後隨機分成兩組：EVL (1 mg bid) /TAC/類固醇和MMF (10-15 mg/kg bid) /TAC/類固醇，且調整TAC劑量以達到目標谷濃度 (Ctrough) 8-12 ng/mL，當TAC與EVL血中濃度達穩定狀態後，分別在給藥前及給藥後1、2、3、5、8、12小時抽血，TAC全血濃度以延遲性一步驟免疫分析法 (delayed one-step immunoassay) 測定，EVL全血濃度以免疫濁度法 (turbidimetric immunoassay) 測定。藥動學參數使用WinNonLin的non-compartmental analysis計算；統計分析方法，在連續性變項使用independent t-test，類別變項使用Fisher’s exect test，相關性使用Spearman rank correlation分析。

結果：
本研究納入15位病人，其中三位分別因為輸尿管狹窄、腸胃道出血和未遵守protocol退出研究，最後共有12位病人完成試驗；兩組病人的年齡、性別、體重、肝腎功能、白蛋白沒有差異；TAC劑量在EVL組需為MMF組的2倍 (5.0±1.3 vs. 2.5±0.7 mg bid，p <0.01) 才能達到目標Ctrough。與MMF組相比，EVL組的TAC劑量校正Ctrough低61% (1.23±0.32 vs. 3.13±1.15 ng/mL/mg，p = 0.009)、TAC劑量校正濃度-時間曲線下面積 (area under the curve，AUC0-12) 低47% (29.00±6.22 vs. 55.14±17.32 hr*ng/mL/mg，p = 0.012)、TAC劑量校正峰濃度 (Cmax) 低37% (5.32±1.31 vs. 8.48±1.85 ng/mL/mg，p = 0.009)、TAC口服清除率 (CL/F) 高51% (0.62±0.12 vs. 0.41±0.20 ng/mL/mg，p = 0.044)。此外，MMF組的TAC Ctrough與AUC0-12線性相關性較EVL組高 (r = 0.94 vs. 0.66)，所有病人在給藥後第5小時血中濃度 (C5) 與AUC0-12相關性最高。

結論：
在新腎臟移植病人，使用TAC/EVL/類固醇比起TAC/MMF/類固醇，TAC的體內暴露量低61%，且TAC併用EVL比起併用MMF，需要2倍劑量來達到相同目標Ctrough；因此，若TAC在合併EVL或MMF治療之間作轉換，TAC的Ctrough須密切監測，且TAC劑量須調整。

關鍵字

tacrolimus ； everolimus ； mycophenolate mofetil ； 腎移植 ； 藥品動態學 ； 藥品交互作用 ； 免疫抑制劑

並列摘要

Introduction:
Studies on the effect of everolimus (EVL) on tacrolimus (TAC) pharmacokinetics (PK) were limited and the results were inconsistent. In contrast, studies showed that mycophenolate mofetil (MMF) had limited effect on tacrolimus PK. This study investigated the influence of EVL on TAC PK, using MMF-TAC combination as a control.

Methods:
This was a prospective, randomized, open-label study. De novo renal transplant recipients aged 20-65 years were included. Exclusion criteria were pregnancy, retransplantation or multiorgan transplantation, positive for human immunodeficiency virus, hepatitis B or C virus, aminotransferase level ≥ 2 times the upper limit of normal, and history of rheumatoid arthritis. Patients were randomized to receive either EVL (1 mg bid) or MMF (10-15 mg/kg bid) in combination with TAC and corticosteroids. Doses of TAC were adjusted to maintain trough concentration in the range of 8-12 ng/mL. Steady-state PK profiles of TAC and EVL using whole blood sample were taken just before and 1, 2, 3, 5, 8, 12 hour after drug administration. TAC and EVL were analyzed in whole blood sample by delayed one-step immunoassay and tturbidimetric immunoassay respectively. PK parameters were evaluated by noncompartmental methods using WinNonLin. Continuious and categorical variables were analyzed with unpaired two-tailed t test and Fisher’s exact test, respectively. Correlations were analyzed with Spearman’s correlation coefficient.

Results:
Fifteen patients were enrolled in the study. Three patients dropped out because of ureteral stenosis, gastrointestinal bleeding or protocol violation; thus, 12 patients completed the study. There were no significant differences in age, gender, weight, renal function, liver function, and albumin level between the two groups.TAC dosage required to maintain the same target trough concentration (Ctrough) in EVL group was 2 times higher than in MMF group (5.0±1.3 vs. 2.5±0.7 mg bid，p <0.01). Compared to MMF group, dose-normalized TAC Ctrough was 61% lower (1.23±0.32 vs. 3.13±1.15 ng/mL/mg，p = 0.009) and dose-normalized TAC area under the curve (AUC0-12) was 47% lower (29.00±6.22 vs. 55.14±17.32 hr*ng/mL/mg，p = 0.012) in EVL group. In EVL group, dose-normalized TAC peak concentration (Cmax) was 37% lower (5.32±1.31 vs. 8.48±1.85 ng/mL/mg，p = 0.009) and TAC oral clearance (CL/F) was 51% higher (0.62±0.12 vs. 0.41±0.20 ng/mL/mg，p = 0.044) than those in MMFgroup. In addition, we observed a better linear correlation between TAC Ctrough and AUC0-12 in MMF group than that in EVL group (r = 0.94 vs. 0.66). TAC concentration at 5 hour after drug administration (C5) correlated the best with AUC0-12 in all patients.

Conclusion:
In de novo renal transplant recipients, when combined with EVL, TAC exposure was 61% lower than when combined with MMF. TAC dosage had to be doubled to maintain same target Ctrough in everolimus-treated patients than in MMF-treated patients. TAC dosage should be adjusted, and Ctrough should be closely monitored when switch between EVL and MMF combination.

並列關鍵字

tacrolimus ； everolimus ； mycophenolate mofetil ； kidney transplant ； pharmacokinetics ； drug interaction ； immunosuppressants

參考文獻

1. Johnson HJ, Schonder KS. Solid-organ transplantation. In: Dipiro JT, Talbert RT, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: a pathophysiologic approach. 8th ed. New York: McGraw-Hill; 2011:1537-58.

2. KDIGO clinical practice guideline for the care of kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 2009;9 Suppl 3:S1-155.

3. Christians U, Jacobsen W, Benet LZ, Lampen A. Mechanisms of clinically relevant drug interactions associated with tacrolimus. Clinical pharmacokinetics 2002;41:813-51.

4. Izuishi K, Wakabayashi H, Ohnishi T, Maeta H, Maeba T, Ichikawa Y. Effects of an immunosuppressive agent, tacrolimus (FK-506), on the activities of cytochrome P-450-linked monooxygenase systems in rat liver microsomes. The international journal of biochemistry cell biology 1997;29:921-8.

5. Hoof T, Demmer A, Christians U, Tummler B. Reversal of multidrug resistance in Chinese hamster ovary cells by the immunosuppressive agent rapamycin. European journal of pharmacology 1993;246:53-8.