Chen Cuiping, Bujanover Shay, Gupta Anita
Research & Development, Depomed Inc., Newark, California.
Vice Chair, Associate Professor, Division of Pain Medicine and Regional Anesthesiology, Department of Anesthesiology and Perioperative Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania.
J Opioid Manag. 2015 Mar-Apr;11(2):139-46. doi: 10.5055/jom.2015.0263.
To evaluate the effects of different dosing intervals on multiple-dose pharmacokinetics, and safety and tolerability of fentanyl pectin nasal spray (FPNS).
This was an open-label study in healthy volunteers. Five FPNS treatments (1 × 100 μg; 2 × 100 μg at 4-, 2-, and 1-hour intervals, and 8 × 100 μg consecutively) were administered to the right nostril, with a ≥ 3-day washout period. Blood samples were collected at predose and up to 1,440 minutes postdose. Plasma fentanyl concentrations were determined. Pharmacokinetic parameters-peak concentration (C(max)), time to C(max) (t(max)), and area under the concentration-time curve (AUC)-were derived using noncompartmental method. For the two-dose regimens, pharmacokinetic parameters were compared between doses using a paired t-test with p < 0.05 as statistically significant.
Thirteen subjects were enrolled and 10 completed the study. Median tmax was 10-15 minutes across five regimens. Cmax post the second dose significantly increased for 1-hour (p < 0.0001) and 2-hour (p < 0.001) but not 4-hour intervals (p = 0.462). C(max) and AUC(0-24) following 8 × 100 μg were approximately fivefold of those following 1 × 100 μg. Dizziness (11.9 percent) and somnolence (4.9 percent) were most common adverse events (AEs). 12.9 percent of patients discontinued due to AEs.
FPNS exhibited consistently rapid t(max). When intervals between two doses were shorter, the difference in C(max) between the first and second dose was larger. All regimens of FPNS were well tolerated. Exposure reached a plateau after eight consecutive doses, suggesting potential limited absorption through the nasal mucosa.
评估不同给药间隔对多剂量芬太尼果胶鼻喷雾剂（FPNS）药代动力学、安全性和耐受性的影响。
这是一项针对健康志愿者的开放标签研究。五种FPNS治疗方案（1×100μg；2×100μg，间隔4小时、2小时和1小时，以及连续8×100μg）经右鼻孔给药，洗脱期≥3天。给药前及给药后长达1440分钟采集血样。测定血浆芬太尼浓度。采用非房室模型方法推导药代动力学参数——峰浓度（C(max)）、达峰时间（t(max)）和浓度-时间曲线下面积（AUC）。对于两剂量方案，采用配对t检验比较各剂量间的药代动力学参数，p<0.05为具有统计学显著性。
纳入13名受试者，10名完成研究。五种方案的tmax中位数均为10 - 15分钟。第二剂给药后的Cmax在1小时（p<0.0001）和2小时（p<0.001）间隔时显著升高，但4小时间隔时未升高（p = 0.462）。8×100μg后的C(max)和AUC(0 - 24)约为1×100μg后的五倍。头晕（11.9%）和嗜睡（4.9%）是最常见的不良事件（AE）。12.9%的患者因AE停药。
FPNS的tmax始终较快。两剂之间的间隔越短，第一剂和第二剂之间的Cmax差异越大。FPNS的所有方案耐受性良好。连续八剂后暴露达到平台期，提示经鼻黏膜吸收可能存在潜在限制。
