Servicio de Nefrología, Hospital del Mar, Barcelona, Spain.
Transplantation. 2010 Apr 27;89(8):994-1000. doi: 10.1097/TP.0b013e3181ccd7f2.
Clinical data are lacking concerning therapeutic action and systemic exposure of tacrolimus (TAC) and everolimus (EVL) in a combined regimen in renal transplantation.
A prospective randomized phase II pharmacokinetic study was conducted comparing two fixed EVL dosages (0.75 mg two times per day (BID), group A, or 1.5 mg BID, group B) in combination with standard TAC dose. Complete 12-hr pharmacokinetic curves of both drugs were performed at days 4, 14, and 42 posttransplant.
A higher TAC Cmin was observed with EVL dose of 0.75 mg BID (TAC 11.1+/-6.4 group A vs. 9.4+/-5.0 ng/mL group B, P=0.03), with equivalent TAC area under the curves (162+/-61 vs. 171+/-75). The exposure to TAC was lower in group B despite higher TAC doses were required to maintain target concentrations (day 14: 9.5 vs. 12.5 mg and day 42: 6 vs. 9 mg, P<0.05). Cmin-TAC/dose and area under the curve-TAC/dose ratios were significantly lower, from day 4 to day 42, in group B. Both groups achieved good graft function and acute rejection rate was similar (20% and 15%, respectively).
We conclude that in adult renal transplant recipients, EVL significantly decreases TAC oral bioavailability in a dose-dependent manner. Doses higher than 1.5 mg BID would be probably needed for TAC-minimization strategies because 3 mg/day is not enough to achieve levels more than 3 ng/mL during the first 2 weeks. Therapeutic drug monitoring is mandatory to adjust the dose and prevent low TAC exposure. This regimen of low EVL exposure plus standard TAC exposure avoids wound healing problems with good efficacy.
在肾移植中，联合应用他克莫司（TAC）和依维莫司（EVL）的治疗作用和全身暴露情况缺乏临床数据。
进行了一项前瞻性随机 II 期药代动力学研究，比较了两种固定 EVL 剂量（每天两次 0.75 毫克[BID]，A 组或每天两次 1.5 毫克[BID]，B 组）与标准 TAC 剂量联合应用的情况。在移植后第 4、14 和 42 天进行了两种药物的完整 12 小时药代动力学曲线。
与 EVL 0.75 mg BID 剂量组（TAC 11.1±6.4 组 A 与 9.4±5.0 ng/mL 组 B，P=0.03）相比，观察到 EVL 剂量为 0.75 mg BID 时 TAC 的 Cmin 更高，而 TAC 的 AUC 则相当（162±61 与 171±75）。尽管需要更高的 TAC 剂量来维持目标浓度，但 B 组的 TAC 暴露量较低（第 14 天：9.5 与 12.5 mg；第 42 天：6 与 9 mg，P<0.05）。从第 4 天到第 42 天，B 组的 Cmin-TAC/剂量和 AUC-TAC/剂量比值均显著降低。两组均获得了良好的移植物功能，急性排斥反应率相似（分别为 20%和 15%）。
我们得出结论，在成年肾移植受者中，EVL 以剂量依赖性方式显著降低 TAC 的口服生物利用度。因为在最初 2 周内，3 毫克/天不足以达到 3ng/ml 以上的水平，所以可能需要 1.5 毫克 BID 以上的剂量来实现 TAC 最小化策略。需要进行治疗药物监测以调整剂量并防止 TAC 暴露不足。这种低 EVL 暴露加标准 TAC 暴露的方案避免了与伤口愈合相关的问题，并具有良好的疗效。
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