Felipe Claudia R, Oliveira Nagilla I, Hannun Pedro G, de Paula Mayara Ivani, Tedesco-Silva Helio, Medina-Pestana Jose O
Hospital do Rim, Universidade Federal de São Paulo, Nephrology division, Brazil.
Ther Drug Monit. 2016 Feb;38(1):64-72. doi: 10.1097/FTD.0000000000000236.
Conversion from cyclosporine (CsA) to everolimus (EVR) in kidney transplant recipients receiving mycophenolate sodium (MPS) and corticosteroids has been used to reduce CsA associated toxicities. Nevertheless, exposures produced by the initial EVR dose, the steady state pharmacokinetic and long-term safety and tolerability have not been explored in detail.
Twenty-four stable kidney transplant recipients receiving CSA, MPS, and corticosteroids were converted from CSA to EVR. The initial EVR dose was 3 mg BID. Weekly monitoring of EVR blood concentrations was followed by a full 12 hour pharmacokinetic profile 28 days after conversion. Therapeutic drug monitoring, safety, and tolerability were analyzed during 5 years of follow-up.
The study population was relatively young (mean of 42 years) with a predominance of males (62%) and White (67%) recipients of kidneys from living (54%) or deceased (46%) donors. Mean time of the conversion was 61 months after transplantation. In the first 7 patients, the initial EVR dose of 3 mg BID resulted in mean EVR trough blood concentration of 14.7 ± 3.7 ng/mL at day 7. The initial EVR dose was then reduced to 2 mg BID for the following 17 patients. Four weeks after conversion, mean EVR dose was 1.7 ± 0.5 mg BID (7 patients were receiving 1 mg BID and 17 were receiving 2 mg BID) resulting in mean EVR trough blood concentration of 4.0 ± 1.4 ng/mL. Whereas mean maximum concentration (13.4 ± 2.8 versus 22.9 ± 7.4 ng/mL, P = 0.003) and mean apparent clearance (232 ± 79 versus 366 ± 173 mL/min, P = 0.016) were higher, mean area under the curve (78.2 ± 22.1 versus 102.5 ± 38.5 ng.h/mL, P = 0.067) and mean C0 (3.7 ± 1.3 versus 4.1 ± 1.5 ng/mL, P = 0.852) were no different comparing patients receiving 1 mg and 2 mg EVR BID. Mean inter-subject variability of area under the curve, trough concentration, and maximum concentration was 38%, 36%, and 38%. EVR treatment was discontinued in 29% of patients due to proteinuria (N = 2), pneumonia (N = 2), dyslipidemia (N = 2), and anemia (N = 1) and MPS dose was reduced in 58% of patients.
The initial 3 mg BID dose produced high EVR trough blood concentrations. The 2 mg BID dose appears to be the appropriate initial dose to provide therapeutic concentrations but still requires initial intensive therapeutic monitoring to achieve and maintain blood concentrations within the therapeutic target concentration. The combination of EVR and full dose MPS has limited long-term tolerability and safety.
在接受霉酚酸钠（MPS）和皮质类固醇治疗的肾移植受者中，将环孢素（CsA）转换为依维莫司（EVR）已被用于降低与CsA相关的毒性。然而，初始EVR剂量产生的暴露量、稳态药代动力学以及长期安全性和耐受性尚未得到详细研究。
24名接受CSA、MPS和皮质类固醇治疗的稳定肾移植受者从CSA转换为EVR。初始EVR剂量为每日两次，每次3毫克。转换后28天，在每周监测EVR血药浓度后进行完整的12小时药代动力学分析。在5年的随访期间分析治疗药物监测、安全性和耐受性。
研究人群相对年轻（平均42岁），以男性（62%）和白人（67%）为主，接受来自活体（54%）或 deceased（46%）供体的肾脏移植。转换的平均时间为移植后61个月。在前7名患者中，初始EVR剂量每日两次，每次3毫克，导致第7天的平均EVR谷血浓度为14.7±3.7纳克/毫升。随后，对其余17名患者将初始EVR剂量降至每日两次，每次2毫克。转换四周后，平均EVR剂量为每日两次，每次1.7±0.5毫克（7名患者每日两次，每次1毫克，17名患者每日两次，每次2毫克），导致平均EVR谷血浓度为4.0±1.4纳克/毫升。接受每日两次1毫克和2毫克EVR的患者相比，平均最大浓度（13.4±2.8对22.9±7.4纳克/毫升，P = 0.003）和平均表观清除率（232±79对366±173毫升/分钟，P = 0.016）较高，但平均曲线下面积（78.2±22.1对102.5±38.5纳克·小时/毫升，P = 0.067）和平均C0（3.7±1.3对4.1±1.5纳克/毫升，P = 0.852）无差异。曲线下面积、谷浓度和最大浓度的平均个体间变异性分别为38%、36%和38%。29%的患者因蛋白尿（N = 2）、肺炎（N = 2）、血脂异常（N = 2）和贫血（N = 1）而停用EVR治疗，58%的患者减少了MPS剂量。
初始每日两次，每次3毫克的剂量产生了较高的EVR谷血浓度。每日两次，每次2毫克的剂量似乎是提供治疗浓度的合适初始剂量，但仍需要初始强化治疗监测，以实现并维持血药浓度在治疗目标浓度范围内。EVR与全剂量MPS联合使用的长期耐受性和安全性有限。
