Niu Yulin, Lan Gongbin, Wang Jina, Yan Tianzhong, Jin Peng
Department of Organ Transplantation, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Department of Kidney Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China.
Transpl Immunol. 2023 Dec;81:101933. doi: 10.1016/j.trim.2023.101933. Epub 2023 Sep 18.
The demand for generic tacrolimus is enormous. Our randomized trial was an open-label single-dose testing with four-periods and two-sequences; we aimed to evaluate the bioequivalence between a generic and branded tacrolimus by establishing their area under concentration-time curve (AUC) predictive equations. For better comparison, each tacrolimus served either as test vs. reference in sequence 1 or vice versa as reference vs. test in sequence 2.
Forty healthy subjects were randomized into two groups, namely a sequence 1 group (N = 20 in test-reference-test-reference) or sequence 2 (N = 20, reference-test-reference-test) received a test tacrolimus (Ruibeirong®; Chengdu Shengdi Medicine Co., Ltd.) and a reference tacrolimus (Astagraf XL®, Astellas Ireland Co., Ltd.) under the fasting condition with a wash-out period of ≥14 days between every two phases. Blood samples were collected sequentially until 120 h after oral administration of tacrolimus.
A 95% upper confidence bound was -0.05% for the peak concentration (C), -0.02% for the AUC from 0 to the last time point (AUC), and - 0.02% for the AUC from 0 to infinity (AUC). The geometric least square means ratio (test/reference) with 90% of confidence interval (CI)) was 96.10% (90.58%-101.95%) for C, 93.80% (88.52%-99.39%) for AUC, and 94.34% (89.20%-99.77%) for AUC. Meanwhile, the ratio of within-subject standard deviation of test/reference (σ) with 90% CI was 0.66 (0.50-0.86) for C, 0.73 (0.55-0.96) for AUC, and 0.75 (0.57-0.98) for AUC. These results fulfilled the bioequivalence criteria by the Food and Drug Administration. Both products showed acceptable safety. Moreover, the AUC predictive equations (by linear regression plus limited sampling strategy) with 2-5 sampling time point showed the high performance (all R > 0.970, predictive error (PE) >0.5%, absolute PE <5.1%, which were interchangeable between test and reference products.
Generic tacrolimus (Ruibeirong®) is bioequivalent to branded tacrolimus (Astagraf XL®) with tolerable safety, which AUC predictive equations work well and are interchangeable between the two products.
对他克莫司仿制药的需求巨大。我们的随机试验是一项开放标签的单剂量四周期两序列试验；我们旨在通过建立浓度-时间曲线下面积（AUC）预测方程来评估他克莫司仿制药与品牌药之间的生物等效性。为了更好地比较，每种他克莫司在序列1中作为受试制剂与参比制剂，在序列2中则相反作为参比制剂与受试制剂。
40名健康受试者被随机分为两组，即序列1组（N = 20，受试-参比-受试-参比）或序列2组（N = 20，参比-受试-参比-受试），在禁食条件下接受受试他克莫司（瑞倍荣®；成都盛迪医药有限公司）和参比他克莫司（安斯泰来XL®，安斯泰来爱尔兰有限公司），每两个阶段之间有≥14天的洗脱期。在口服他克莫司后依次采集血样直至120小时。
峰浓度（C）的95%置信上限为-0.05%，0至最后一个时间点的AUC（AUC）为-0.叭%，0至无穷大的AUC（AUC）为-0.02%。C的几何最小二乘均值比（受试/参比）及90%置信区间（CI）为96.10%（90.58%-101.95%），AUC为93.80%（88.52%-99.39%），AUC为94.34%（89.20%-99.77%）。同时，受试/参比的个体内标准差比（σ）及90%CI，C为0.66（0.50-0.86），AUC为0.73（0.55-0.96），AUC为0.75（0.57-0.98）。这些结果符合美国食品药品监督管理局的生物等效性标准。两种产品均显示出可接受的安全性。此外，具有2-5个采样时间点的AUC预测方程（通过线性回归加有限采样策略）表现出高性能（所有R>0.970，预测误差（PE）>0.5%，绝对PE<5.1%），受试产品和参比产品之间可互换。
他克莫司仿制药（瑞倍荣®）与品牌他克莫司（安斯泰来XL®）具有生物等效性，安全性可耐受，其AUC预测方程效果良好且两种产品之间可互换。
