From P Less Than, San Francisco, California (D.M.F.); Certara Strategic Consulting, Princeton, New Jersey (P.C., D.R.W.); Leiden University Medical Center, Leiden, The Netherlands (A.D.); and AcelRx Pharmaceuticals, Redwood City, California (P.P.P.).
Anesthesiology. 2018 May;128(5):943-952. doi: 10.1097/ALN.0000000000002145.
Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described.
Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used.
Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment.
The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.
在许多医学监管环境中，治疗中重度急性疼痛的理想产品属性是起效迅速，且无需静脉通路的给药途径。本文描述了舌下含服 15 或 30μg 舒芬太尼片剂的药代动力学特征。
健康受试者（四项研究，122 例）和患者（七项研究，944 例）进行了采血。健康受试者的研究旨在确定生物利用度、细胞色素 P450 3A4 抑制的影响，以及单次和每小时舌下剂量的血浆浓度曲线。患者研究评估了体重、年龄、性别和器官损伤对表观清除率的影响。采用非房室和混合效应群体方法。
单次舌下片剂的生物利用度为 52%，重复给药后降至 35%。酮康唑（CYP3A4 抑制剂）使最大血浆浓度增加 19%，使 AUC 增加 77%。单次给予 30μg 剂量后，血浆浓度在 30 分钟内达到舒芬太尼的镇痛阈（24pg/ml），1 小时达峰，然后在 3 小时内降至治疗浓度以下。每小时给药时，第五次给药后血浆浓度达到平台期。从最大浓度下降 50%的时间与单次给药（2.5±0.85h）和 12 次给药（2.5±0.72h）相似。清除率随体重增加而增加，随年龄增长而降低，且不受肾功能或肝功能损害的影响。
单次 30μg 剂量的时间过程与临床试验中观察到的镇痛起效时间和重复给药频率一致。舌下含服舒芬太尼片剂为在监测环境中非侵入性和快速治疗中重度疼痛提供了机会。
