Pharmacokinetics of inhaled liposome-encapsulated fentanyl

Abstract

Background: Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are microscopic phospholipid vesicles that can entrap drug molecules. Liposomal delivery of fentanyl has the potential to control the uptake of fentanyl by the lungs and thus provide sustained drug release. To demonstrate that inhalation of a mixture of free and liposome-encapsulated fentanyl can provide a rapid increase and sustained plasma fentanyl concentrations (C(fen)s), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in healthy volunteers. Methods: After obtaining institutional approval and informed consent, ten healthy volunteers (five men, five women) were studied. Each subject received 200 μg intravenous fentanyl and inhaled 2,000 μg of a mixture of free (50%) and liposome-encapsulated fentanyl (50%) on separate occasions. Frequent venous blood samples were collected, and C(fen)s were determined by radioimmunoassay. The pharmacokinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analysis and least-squares numeric deconvolution. Results: The mean (±SD) volume of distribution at steady-state and clearance of fentanyl after the intravenous administration were comparable to previous studies: 435 ± 182 l and 0.584 ± 0.209 l · min-1, respectively. The mean (±SD) peak C(fen) was significantly greater for the intravenous administration compared to the aerosol mixture of free and liposome-encapsulated fentanyl (4.67 ± 1.87 vs. 1.15 ± 0.36 ng · ml-1). However, C(fen)s at 8 and 24 h after aerosol administration were greater compared to intravenous (0.25 ± 0.14 and 0.12 ± 0.16 ng · ml-1 for aerosol versus 0.16 ± 0.10 and 0.05 ± 0.06 ng · ml-1 for intravenous). The peak absorption rate, time to peak absorption, and bioavailability after inhalation were 7.02 (±2.34) μg · min,-1 16 (±8.0) min, and 0.12 (±0.11), respectively. Conclusions: The data suggest that this analgesic method offers a simple and noninvasive route of administration with a rapid increase of C(fen) and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the optimal liposome composition that would produce a sustained stable C(fen) within analgesic therapeutic concentrations.