Alloway Rita R, Trofe-Clark Jennifer, Brennan Daniel C, Kerr Janice, Cohen Elizabeth A, Meier-Kriesche Ulf, Stevens Daniel R, Moten Misbah A, Momper Jeremiah D
College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Department of Pharmacy, Hospital of the University of Pennsylvania and Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
Ther Drug Monit. 2020 Oct;42(5):679-685. doi: 10.1097/FTD.0000000000000773.
A modified-release version of tacrolimus, LCP-tacrolimus (LCPT; Envarsus XR, Veloxis Pharmaceuticals, Cary, NC), has been licensed in the United States for prophylaxis of organ rejection in de novo kidney transplant patients. As tacrolimus has a narrow therapeutic window, the impact of circadian patterns on LCPT drug exposure, including food and chronopharmacokinetic effects, needs to be elucidated to optimize dosing.
Two randomized, crossover, phase 1 studies were conducted in healthy volunteers. The first assessed the effect of morning versus evening dosing on the pharmacokinetic profile of LCPT 2 mg; the second assessed the effect of food on the pharmacokinetic profile of LCPT 5 mg. In both, blood samples were drawn from participants for up to 144 hours after administration of a single LCPT dose.
No significant differences were observed between evening and morning dosing in peak blood concentration (4.4 versus 4.0 ng/mL; P = 0.27), area under the time-concentration curve (AUC) from time 0 to time of the last concentration (89.1 versus 102.6 ng/mL; P = 0.20), AUC from time 0 to infinity (99.7 versus 114.3 ng·h/mL; P = 0.18), AUC from 0 to 24 hours post-dose (AUC0-24; 49.4 versus 51.6 ng·h/mL; P = 0.56), time to reach maximum blood concentration (median, 6.0 versus 6.0 hours; P = 0.91), total clearance (arithmetic mean = 21.5 versus 19.5 L/h; P = 0.50), or terminal half-life (arithmetic mean = 26.8 versus 28.1 hours; P = 0.26). After a high-calorie meal in the morning, the AUC0-24 reduced by 54% (ratio of geometric means = 45.6%; P < 0.0001) and peak blood concentration reduced by 22% (ratio of geometric means = 78.4%; P = 0.0006). However, the terminal half-life did not differ between fasted and fed states (33.3 versus 34.8 hours; P = 0.16), implying that these differences occurred because of altered bioavailability rather than modified clearance.
For LCPT, no chronopharmacokinetic effects were observed, whereas food significantly reduced the 24-h exposure and the peak blood concentration.
他克莫司的缓释剂型，即LCP - 他克莫司（LCPT；Envarsus XR，Veloxis制药公司，北卡罗来纳州卡里），已在美国获批用于预防初次肾移植患者的器官排斥反应。由于他克莫司的治疗窗较窄，需要阐明昼夜节律模式对LCPT药物暴露的影响，包括食物和时辰药代动力学效应，以优化给药方案。
在健康志愿者中进行了两项随机、交叉的1期研究。第一项评估了早晨给药与晚上给药对2mg LCPT药代动力学特征的影响；第二项评估了食物对5mg LCPT药代动力学特征的影响。在两项研究中，在单次给予LCPT剂量后，从参与者身上采集血样长达144小时。
晚上给药和早晨给药在血药峰浓度（4.4对4.0 ng/mL；P = 0.27）、从0时到最后浓度时间的时间 - 浓度曲线下面积（AUC）（89.1对102.6 ng/mL；P = 0.20）、从0时到无穷大的AUC（99.7对114.3 ng·h/mL；P = 0.18）、给药后0至24小时的AUC（AUC0 - 24；49.4对51.6 ng·h/mL；P = 0.56）、达到血药峰浓度的时间（中位数，6.0对6.0小时；P = 0.91）、总清除率（算术平均值 = 21.5对19.5 L/h；P = 0.50）或末端半衰期（算术平均值 = 26.8对28.1小时；P = 0.26）方面均未观察到显著差异。早晨进食高热量餐后，AUC0 - 24降低了54%（几何均值比 = 45.6%；P < 0.0001），血药峰浓度降低了22%（几何均值比 = 78.4%；P = 0.0006）。然而，禁食和进食状态下的末端半衰期没有差异（33.3对34.8小时；P = 0.16），这意味着这些差异是由于生物利用度改变而非清除率改变所致。
对于LCPT，未观察到时辰药代动力学效应，而食物显著降低了24小时暴露量和血药峰浓度。
