Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain. (May 2018)

• Record Type: Journal Article
• Authors: Fisher, Dennis M.; Chang, Peter; Wada, D. Russell; Dahan, Albert; Palmer, Pamela P.
• Is Part Of: Anesthesiology. Volume 128:Number 5(2018)
• Publication Date: 2018-05
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000002145
• Languages: English
• ISSNs: 0003-3022

Abstract

Abstract : Background: 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. Methods: 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. Results: 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. Conclusions: 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. Abstract : With sublingual administration of a newly developed 30-μg sufentanil tablet, the time to maximum plasma concentration was approximately 1 h, but the analgesic threshold was typically reached at or before 30 min, which is consistent with the onset of analgesia observed in clinical trials of the 30-μg product. The time for the plasma concentrations to decrease below the analgesic threshold after a single 30-μg dose was approximately 3 h, which is consistent with the duration of analgesia in those published clinical trials.