Darwish Mona, Tempero Kenneth, Jiang John G, Thompson Jeffrey, Simonson Philip G
Arch Drug Inf. 2008 Sep;1(2):43-49. doi: 10.1111/j.1753-5174.2008.00007.x.
This study was conducted to assess the dose proportionality, safety, and tolerability of fentanyl buccal tablet (FBT) in Japanese volunteers. METHODS: Healthy, opioid-naive Japanese adults received single-dose FBT 100, 200, 400, and 800 microg in a randomized, open-label, crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Peak serum fentanyl concentration (C(max)), time to C(max) (t(max)), area under the serum fentanyl concentration-time curve (AUC) from time 0 to infinity (AUC(0-infinity)), and AUC from 0 to the last quantifiable concentration (AUC(0-last)) were summarized using descriptive statistics. Dose proportionality was claimed if the ln-ln plots of C(max), AUC(0-infinity), and AUC(0-last) vs. dose were linear and the 90% confidence intervals (CI) of the slopes were within 0.8927 and 1.1073. The safety population comprised volunteers who received >/=1 FBT. RESULTS: Twenty-five volunteers were enrolled, 23 were included in the safety population (mean age 35.3 years), and 19 completed the study. The assessment of dose proportionality did not meet the statistical criteria (slope [90% CI]: 0.9118 [0.8601, 0.9635] for C(max), 1.0756 [1.0377, 1.1136] for AUC(0-infinity), and 1.0992 [1.0677, 1.1307] for AUC(0-last)). However, the increase in systemic exposure with dose appeared linear, and a post hoc analysis of partial AUCs from time 0 to 8, 12, 18, and 24 hours supported dose proportionality. Median t(max) of 90 minutes (range 30-180 minutes) was independent of dose. Adverse events (AEs) were mild or moderate. The most frequent AEs were nausea (N = 9), dizziness (N = 8), headache (N = 6), somnolence (N = 6), dyspepsia (N = 5), and vomiting (N = 3). No application-site or serious AEs were reported. CONCLUSIONS: Systemic exposure to FBT was approximately dose proportional across the range 100 microg to 800 microg in healthy Japanese adults. Adverse events were mild or moderate.
本研究旨在评估芬太尼口腔崩解片（FBT）在日本志愿者中的剂量比例关系、安全性和耐受性。方法：健康、未使用过阿片类药物的日本成年人以随机、开放标签、交叉方式接受100、200、400和800微克的单剂量FBT。给予纳曲酮以尽量减少芬太尼的阿片类效应。使用描述性统计总结血清芬太尼峰值浓度（C(max)）、达到C(max)的时间（t(max)）、从时间0至无穷大的血清芬太尼浓度-时间曲线下面积（AUC(0-无穷大)）以及从0至最后可定量浓度的AUC（AUC(0-最后)）。如果C(max)、AUC(0-无穷大)和AUC(0-最后)与剂量的对数-对数图呈线性，且斜率的90%置信区间（CI）在0.8927和1.1073之间，则认为存在剂量比例关系。安全人群包括接受≥1剂FBT的志愿者。结果：招募了25名志愿者，23名纳入安全人群（平均年龄35.3岁），19名完成研究。剂量比例关系评估未达到统计标准（斜率[90%CI]：C(max)为0.9118[0.8601,0.9635]，AUC(0-无穷大)为1.0756[1.0377,1.1136]，AUC(0-最后)为1.0992[1.0677,1.1307]）。然而，全身暴露随剂量的增加呈线性，并且对0至8、12、18和24小时的部分AUC进行的事后分析支持剂量比例关系。中位数t(max)为90分钟（范围30 - 180分钟），与剂量无关。不良事件（AE）为轻度或中度。最常见的AE为恶心（N = 9）、头晕（N = 8）、头痛（N = 6）、嗜睡（N = 6）、消化不良（N = 5）和呕吐（N = 3）。未报告应用部位或严重AE。结论：在健康日本成年人中，100微克至800微克范围内，FBT的全身暴露大致呈剂量比例关系。不良事件为轻度或中度。
