肾移植受者中降低他克莫司缓释剂型暴露量的安全性和有效性：一项亚洲-OPTIMIZE研究中的随机、开放标签的试点研究
Safety and Efficacy of Reduced Prolonged-release Tacrolimus Exposure in De Novo Kidney Transplantation: A Randomized, Open-label, Pilot Study in Asia-OPTIMIZE Study.
作者信息
Kim Young Hoon, Chiang Yang-Jen, Kim Sung-Joo, Kim Myoung Soo, Park Sung Bae, Wu Sheng-Tang, Horita Kazuhiro, Nakashima Yoshihiro, Jiang Hongsi, Han Duck-Jong
机构信息
Division of Kidney and Pancreas Transplant, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
Division of Urology, Department of Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan City, Taiwan.
出版信息
Transplant Direct. 2019 Mar 25;5(4):e340. doi: 10.1097/TXD.0000000000000877. eCollection 2019 Apr.
BACKGROUND
A multicenter, randomized, open-label, parallel group, pilot, 52-week study in Asian countries that assessed the renal function, efficacy, and safety of reduced-exposure versus standard-exposure prolonged-release tacrolimus (PR-T) in adult kidney transplant recipients (KTRs).
METHODS
Posttransplantation, KTRs received PR-T from weeks 0 to 4 (initial dose, 0.2-0.3 mg/kg; target trough level, 6-10 ng/mL). At week 4, KTRs were randomized (1:1) to receive reduced-exposure PR-T (target 4-6 ng/mL, weeks 4-12; 3-5 ng/mL, weeks 12-52) or standard-exposure PR-T (target: 6-10 ng/mL, weeks 4-52). Primary end point: estimated glomerular filtration rate (eGFR) over 52 weeks. Secondary end points (week 52) included creatinine clearance, serum creatinine, graft/patient survival, biopsy-confirmed acute rejection (AR), composite of graft loss/patient death/biopsy-confirmed AR, and steroid-resistant AR. Treatment-emergent adverse events were recorded.
RESULTS
Sixty-six KTRs received PR-T (reduced-exposure, n = 32; standard-exposure, n = 34) and were analyzed. After per-protocol dose adjustment, mean ± standard deviation tacrolimus trough level was lower with reduced- versus standard-exposure PR-T (week 52, 4.5 ± 1.1 ng/mL vs 8.0 ± 2.2 ng/mL). In the reduced- versus standard-exposure group, eGFR was similar at weeks 8 to 52 (overall least-square mean difference, -2.82; 95% confidence interval, -7.91 to 2.27; = 0.272). At week 52, there was no significant difference in creatinine clearance ( = 0.375) or serum creatinine ( = 0.547) between groups. All grafts/patients survived, no steroid-resistant AR was reported, and 4 and 3 patients had AR in reduced- and standard-exposure groups, respectively. Drug-related treatment-emergent adverse events were reported in 34.4% and 38.2% of patients, respectively.
CONCLUSIONS
Reducing exposure to PR-T resulted in a clinically acceptable short-term safety profile and was generally as effective as standard tacrolimus exposure for Asian patients.
背景
一项在亚洲国家开展的多中心、随机、开放标签、平行组、先导性、为期52周的研究，评估了成人肾移植受者（KTRs）中低暴露量与标准暴露量的缓释他克莫司（PR-T）的肾功能、疗效和安全性。
方法
肾移植后，KTRs在第0至4周接受PR-T（初始剂量，0.2 - 0.3mg/kg；目标谷浓度，6 - 10ng/mL）。在第4周，KTRs被随机分组（1:1），分别接受低暴露量PR-T（第4 - 12周目标为4 - 6ng/mL，第12 - 52周目标为3 - 5ng/mL）或标准暴露量PR-T（目标：第4 - 52周为6 - 10ng/mL）。主要终点：52周内的估计肾小球滤过率（eGFR）。次要终点（第52周）包括肌酐清除率、血清肌酐、移植物/患者生存率、活检证实的急性排斥反应（AR）、移植物丢失/患者死亡/活检证实的AR的复合指标以及激素抵抗性AR。记录治疗中出现的不良事件。
结果
66例KTRs接受了PR-T（低暴露量组，n = 32；标准暴露量组，n = 34）并进行了分析。经过按方案调整剂量后，低暴露量PR-T组的他克莫司谷浓度均值±标准差低于标准暴露量组（第52周，4.5±1.1ng/mL对8.0±2.2ng/mL）。在低暴露量组与标准暴露量组中相比，第8至52周的eGFR相似（总体最小二乘均值差异，-2.82；95%置信区间，-7.91至2.27；P = 0.272）。在第52周，两组间肌酐清除率（P = 0.375）或血清肌酐（P = 0.547）无显著差异。所有移植物/患者均存活下来，未报告激素抵抗性AR，低暴露量组和标准暴露量组分别有4例和3例患者发生AR。分别有34.4%和38.2%的患者报告了与药物相关的治疗中出现的不良事件。
结论
降低PR-T的暴露量导致了临床上可接受的短期安全性，并且对亚洲患者而言，其总体疗效与标准他克莫司暴露量相当。
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