McAlister V C, Peltekian K M, Malatjalian D A, Colohan S, MacDonald S, Bitter-Suermann H, MacDonald A S
Atlantic Canada Liver Transplantation Program, Dalhousie University, Halifax, Nova Scotia, Canada.
Liver Transpl. 2001 Aug;7(8):701-8. doi: 10.1053/jlts.2001.26510.
Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r(2) = 0.82 and r(2) = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial.
尽管西罗莫司（SRL）比他克莫司（TAC）与亲免素FK506结合蛋白-12（FKBP-12）的结合亲和力更高，但动物研究表明，SRL和TAC具有协同作用以预防排斥反应。与排斥反应相比，剂量相关毒性更常是停用TAC的原因。我们推测，肝移植后SRL可使TAC的联合剂量大幅降低至低于毒性阈值的水平。对56例肝移植受者给予SRL和TAC联合治疗（目标谷浓度分别为7和5 ng/mL）。计划在3个月后开始逐渐停用类固醇。进行了药代动力学（PK）研究。患者和移植物存活率分别为52例患者（93%）和51个移植物（91%），随访23个月（范围6至35个月）。观察到1例（1.8%）肝动脉血栓形成。急性细胞排斥反应发生率为14%。8例患者中有3例未接受额外治疗，其他5例经单一疗程类固醇治疗后缓解。4例患者（7%）发生巨细胞病毒感染。47例患者（84%）在无需额外用药的情况下肾功能、血糖控制和脂质代谢接近正常。51例患者（91%）完成类固醇清除。SRL和TAC的生物利用度在移植受者之间有所不同，但谷浓度与曲线下面积密切相关（分别为r(2)=0.82和r(2)=0.84）。在此剂量下同时给药不影响药物的PK曲线。SRL和TAC的谷浓度与每日剂量之比具有相关性。在动物模型中观察到的协同效应在接受SRL-TAC联合免疫抑制的临床肝移植受者中也存在。在多中心、随机、对照试验中，应将低剂量SRL和TAC联合方案与传统免疫抑制方案进行比较。
