Shumaker Robert, Aluri Jagadeesh, Fan Jean, Martinez Gresel, Ren Min, Chen Kun
Int J Clin Pharmacol Ther. 2014 Apr;52(4):284-91. doi: 10.5414/CP201937.
To evaluate the effect of formulation and a high-fat meal on the pharmacokinetics of orally administered lenvatinib (E7080).
Lenvatinib 10-mg capsule and tablet.
Pharmacokinetics and safety of a single 10-mg lenvatinib dose were evaluated in healthy subjects in two randomized, two-period, crossover, phase 1, bioavailability trials. The first compared a new capsule formulation with an older tablet formulation (n = 20 subjects); the second evaluated the influence of a standard high-fat meal on the relative bioavailability of the capsule formulation (n = 16 subjects). Geometric least squares mean ratios of AUC0-∞, maximum observed concentration (Cmax), and AUC0-t were determined. tmax, tlag (food effect only), and t1/2,z were also calculated, and descriptive statistics were provided.
A total of 36 healthy volunteers were enrolled in the two studies (mean ages 29 and 33 years). In the formulation study, AUC0-∞ and AUC0-t of the capsule formulation were ~ 10% less than the tablet formulation, and Cmax for the capsule formulation was ~ 14% lower. 90% Confidence intervals (CIs) for both AUCs were within the 80 - 125% CI, which is generally considered to denote bioequivalence, while the lower bound of the interval for Cmax was 79.8%. tmax and t1/2,z were comparable. For the capsule formulation, the mean (%CV) t1/2,z was 27.6 hours (27.3) and the median (range) tmax was 2.0 hours (2 - 4). In the food effect study, lenvatinib's AUC0-∞ and AUC0-t increased ~ 6% and 4% with the high-fat meal. Cmax following a high-fat meal was 5% lower than following administration in the fasted state. Administration with food delayed lenvatinib's tmax (2 vs. 4 hours). 90% CIs for AUCs were within the 80 - 125% CI, while the CI for Cmax was 72.1 - 126.4%. The single 10-mg dose demonstrated an acceptable tolerability profile; treatment-emergent adverse events occurred in 9 subjects (25%) overall and were typically mild in severity.
These studies show that a new capsule formulation produces slightly lower exposure (~10 - 14%) to lenvatinib compared with the original tablet formulation, and that oral administration with a high-fat meal does not significantly affect exposure, although absorption is delayed. Thus, lenvatinib can be administered without regard to the timing of meals.
评估制剂和高脂餐对口服乐伐替尼（E7080）药代动力学的影响。
10毫克乐伐替尼胶囊和片剂。
在两项随机、两周期、交叉、1期生物利用度试验中，对健康受试者单次口服10毫克乐伐替尼的药代动力学和安全性进行评估。第一项试验比较了一种新的胶囊制剂和一种旧的片剂制剂（n = 20名受试者）；第二项试验评估了标准高脂餐对胶囊制剂相对生物利用度的影响（n = 16名受试者）。测定了AUC0-∞、最大观察浓度（Cmax）和AUC0-t的几何最小二乘均值比。还计算了tmax、tlag（仅食物效应）和t1/2,z，并提供了描述性统计数据。
两项研究共纳入36名健康志愿者（平均年龄分别为29岁和33岁）。在制剂研究中，胶囊制剂的AUC0-∞和AUC0-t比片剂制剂低约10%，胶囊制剂的Cmax低约14%。两个AUC的90%置信区间（CIs）均在80 - 125%CI内，一般认为这表示生物等效性，而Cmax区间的下限为79.8%。tmax和t1/2,z具有可比性。对于胶囊制剂，平均（%CV）t1/2,z为27.6小时（27.3），中位（范围）tmax为2.0小时（2 - 4）。在食物效应研究中，高脂餐使乐伐替尼的AUC0-∞和AUC0-t分别增加约6%和4%。高脂餐后的Cmax比空腹给药后低5%。与食物一起给药使乐伐替尼的tmax延迟（2小时对4小时）。AUC的90%CI在80 - 125%CI内，而Cmax的CI为72.1 - 126.4%。单次10毫克剂量显示出可接受的耐受性；总体上有9名受试者（25%）出现治疗中出现的不良事件，严重程度通常为轻度。
这些研究表明，与原片剂制剂相比，新的胶囊制剂使乐伐替尼的暴露量略低（约10 - 14%），并且高脂餐口服给药虽吸收延迟但对暴露量无显著影响。因此，乐伐替尼给药无需考虑用餐时间。
