Pharmacokinetics, Safety, and Tolerability of Ascending Doses of Sublingual Fentanyl, With and Without Naltrexone, in Japanese Subjects

Abstract

This open-label, nonrandomized study assessed single and repeat ascending doses of a new sublingual fentanyl (SLF) formulation in 48 healthy Japanese opiate-naïve subjects (47 completed). Subjects received single-dose SLF 100, 200, 400, or 800 µg followed by 13 doses 6 hourly, at their dose level. Subjects taking repeat-dose 400 and 800 µg were pretreated with naltrexone in order to block opiate-receptor-mediated effects on respiration, monitored by pulse oximetry and transcutaneous pco(2). Sublingual fentanyl was rapidly and consistently absorbed. After single doses, median t(first) was 0.08 to 0.25 hours and t(max) 0.50 to 1.00 hours. After repeat dosing, median t(max) (t(max,ss)) was 0.50 to 2.00 hours. Plasma concentrations were dose proportional both after single and repeat dosing, and naltrexone appeared to have no effect on SLF pharmacokinetics. Plasma fentanyl reached steady state within the 72-hour dosing period and accumulation was approximately 2-fold. After single doses, effects on respiratory variables were evident after the 400-µg and 800-µg doses. Transcutaneous pco(2) was not helpful in detecting respiratory depression. Thus, SLF yielded rapid absorption of fentanyl and dose-proportional plasma concentrations that, for 400 µg and 800 µg, were within the typical analgesic range. Respiratory depression in these opioid-naïve volunteers was manageable with simple clinical measures.

A Fentanyl Vaccine Alters Fentanyl Distribution and Protects against Fentanyl-Induced Effects in Mice and Rats

“…In the current study, fentanyl induced respiratory depression at subcutaneous cumulative fentanyl doses above 12.5-25 mg/kg in sKLH-treated and naive rats. In humans, sublingual doses of 800 mg (11 mg/kg in a 70-kg human) caused respiratory depression after 2 hours in all 12 subjects (Lister et al, 2011). In another study (Dahan et al, 2005), apnea was reported in human subjects at an intravenous fentanyl dose as low as 2.9 mg/kg, and that prolonged apnea occurred at 7.1 mg/kg, leading the investigators to halt using this dose for the remainder of the study.…”

A Comprehensive Review of Rapid-Onset Opioids for Breakthrough Pain

“…[79] Subjects received SLF 100, 200, 400 or 800 μg every 6 hours for a total of 14 doses. Subjects administered repeated doses of SLF 400 μg or 800 μg also received naltrexone to prevent opioid-mediated respiratory depression.…”

The Influence of Low Salivary Flow Rates on the Absorption of a Sublingual Fentanyl Citrate Formulation for Breakthrough Cancer Pain

“…The pharmacokinetics of the sublingual fentanyl orally disintegrating tablet have been investigated in normal volunteers, 7,8 and cancer patients. 9 However, there appears to be no data on the pharmacokinetics of sublingual fentanyl orally disintegrating tablets, or indeed other oral transmucosal opioids, in patients with salivary gland hypofunction.…”