Felipe Claudia, Ferreira Alexandra, Bessa Adrieli, Abait Tamiris, Perez Juliana D, Casarini Dulce Elena, Medina-Pestana Jose, Tedesco Helio
Nephrology Division, Hospital do Rim, UNIFESP, São Paulo, Brazil.
Ther Drug Monit. 2018 Feb;40(1):52-58. doi: 10.1097/FTD.0000000000000464.
This study investigates the adequacy of initial everolimus (EVR) dose, with and without calcineurin inhibitors (CNI), in kidney transplant recipients.
This retrospective cohort analysis involved data from 305 kidney transplant recipients participating in 3 randomized trials receiving reduced dose cyclosporin A (CsA) combined with EVR 0.75 mg BID (CSA/EVR0.75, N = 32) or 1.5 mg BID (CSA/EVR1.5, N = 31), reduced dose tacrolimus (TAC) combined with EVR 1.5 mg BID (TAC0.05/EVR1.5, N = 83), standard dose TAC combined with EVR 1.5 mg BID (TAC0.1/EVR1.5, N = 93), and EVR 1.5 mg BID (EVR1.5, N = 66) with TAC introduction after day 5. The adequacy of the initial EVR dose, based on EVR whole blood trough between 3 and 8 ng/mL, was compared using first EVR blood concentrations obtained at day 3 after transplantation.
Recipient age, proportion of patients with diabetes mellitus, and proportion of grafts from living donors were different among the groups. Dose-corrected EVR concentrations were higher in patients receiving CsA than in those receiving TAC or no calcineurin inhibitors (6.7 ± 5.9 versus 5.4 ± 2.2 versus 2.4 ± 0.8 versus 2.5 ± 0.9 versus 2.2 ± 0.7, P = 0.000). No differences were observed comparing dose adjusted EVR concentrations combined with TAC or alone (P = 0.073). The proportion of patients with EVR concentration below <3 ng/mL was lower when EVR was combined with CsA (25 versus 3 versus 43 versus 33 versus 50%, P = 0.000). Later introduction of TAC did not influence EVR concentrations. There were no differences in mean CsA concentrations comparing patients receiving EVR 0.75 or 1.5 mg BID (240 ± 143 versus 213 ± 105 ng/mL). On the other hand, mean TAC concentrations were higher according to the initial TAC dose regimen (6.4 ± 3.9 versus 9.8 ± 5.9 ng/mL).
In de novo kidney transplant recipients, the choice of the initial dose of EVR should consider the type of calcineurin inhibitor to reach target EVR concentration within the first week in a higher proportion of patients, maximizing the efficacy/toxicity profile.
本研究调查肾移植受者中初始依维莫司（EVR）剂量在联合或不联合钙调神经磷酸酶抑制剂（CNI）时是否合适。
这项回顾性队列分析涉及305名肾移植受者的数据，这些受者参与了3项随机试验，接受低剂量环孢素A（CsA）联合EVR 0.75 mg每日两次（CSA/EVR0.75，N = 32）或1.5 mg每日两次（CSA/EVR1.5，N = 31）、低剂量他克莫司（TAC）联合EVR 1.5 mg每日两次（TAC0.05/EVR1.5，N = 83）、标准剂量TAC联合EVR 1.5 mg每日两次（TAC0.1/EVR1.5，N = 93），以及EVR 1.5 mg每日两次（EVR1.5，N = 66）且在第5天后引入TAC。根据移植后第3天获得的首次EVR血药浓度，比较基于3至8 ng/mL的EVR全血谷浓度的初始EVR剂量是否合适。
各组之间受者年龄、糖尿病患者比例以及活体供者移植物比例存在差异。接受CsA的患者中剂量校正后的EVR浓度高于接受TAC或不接受钙调神经磷酸酶抑制剂的患者（6.7±5.9对5.4±2.2对2.4±0.8对2.5±0.9对2.2±0.7，P = 0.000）。比较联合TAC或单独使用时剂量调整后的EVR浓度未观察到差异（P = 0.073）。EVR与CsA联合时EVR浓度低于<3 ng/mL的患者比例较低（25%对3%对43%对33%对50%，P = 0.000）。TAC的延迟引入不影响EVR浓度。接受EVR 0.75或1.5 mg每日两次的患者比较，平均CsA浓度无差异（240±143对213±105 ng/mL）。另一方面，根据初始TAC剂量方案，平均TAC浓度较高（6.4±3.9对9.8±5.9 ng/mL）。
在初发肾移植受者中，选择初始EVR剂量应考虑钙调神经磷酸酶抑制剂的类型，以使更高比例的患者在第一周内达到目标EVR浓度，从而使疗效/毒性特征最大化。
