Pharmacokinetics, safety, and tolerability of ascending doses of sublingual fentanyl, with and without naltrexone, in Japanese subjects

J Clin Pharmacol. 2011 Aug;51(8):1195-204. doi: 10.1177/0091270010379410. Epub 2011 Jan 5.

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorption
  • Administration, Sublingual
  • Adult
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects*
  • Analgesics, Opioid / blood
  • Analgesics, Opioid / pharmacokinetics*
  • Asians
  • Blood Gas Monitoring, Transcutaneous
  • Dose-Response Relationship, Drug
  • Drug Interactions / ethnology
  • Drug Monitoring / methods
  • Female
  • Fentanyl / administration & dosage
  • Fentanyl / adverse effects*
  • Fentanyl / blood
  • Fentanyl / pharmacokinetics*
  • Half-Life
  • Humans
  • Japan / ethnology
  • Male
  • Mouth Mucosa / metabolism
  • Naltrexone / therapeutic use*
  • Narcotic Antagonists / therapeutic use*
  • Receptors, Opioid, mu / agonists*
  • Respiratory Insufficiency / chemically induced
  • Respiratory Insufficiency / diagnosis
  • Respiratory Insufficiency / ethnology
  • Respiratory Insufficiency / prevention & control
  • Tablets
  • Young Adult

Substances

  • Analgesics, Opioid
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • Tablets
  • Naltrexone
  • Fentanyl