PHARMACOKINETICS OF INHALED LIPOSOME-ENCAPSULATED FENTANYL

Background: Pulmonary administration of fentanyl solution can provide satisfactory but brief postoperative pain relief. Liposomes are micros copic phospholipid vesicles that can entrap drug molecules, Liposomal delivery of fentanyl has the potential to control the uptake of fentan yl by the lungs and thus provide sustained drug release. To demonstrat e that inhalation of a mixture of free and liposome-encapsulated fenta nyl can provide a rapid increase and sustained plasma fentanyl concent rations (C(fen)s), this study determined the pharmacokinetic profiles after the inhalation of free and liposome-encapsulated fentanyl in hea lthy volunteers. Methods: After obtaining institutional approval and i nformed consent, ten healthy volunteers (five men, five women) were st udied. Each subject received 200 mu g intravenous fentanyl and inhaled 2,000 mu g of a mixture of free (50%) and liposome-encapsulated fenta nyl (50%) on separate occasions. Frequent venous blood samples were co llected, and C(fen)s were determined by radioimmunoassay. The pharmaco kinetics and absorption characteristics of the inhaled mixture of free and liposome-encapsulated fentanyl were determined using moment analy sis and least-squares numeric deconvolution. Results: The mean (+/-SD) volume of distribution at steady-state and clearance of fentanyl afte r the intravenous administration were comparable to previous studies: 435 +/- 1821 and 0.584 +/- 0.2091 . min(-1), respectively. The mean (/-SD) peak C-fen was significantly greater for the intravenous adminis tration compared to the aerosol mixture of free and liposome-encapsula ted 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 compare d to intravenous (0.25 +/- 0.14 and 0.12 +/- 0.16 ng . ml(-1) for aero sol versus 0.16 +/- 0.10 and 0.05 +/- 0.06 ng . ml(-1) for intravenous ). The peak absorption rate, time to peak absorption, and bioavailabil ity after inhalation were 7.02 (+/-2.34) mu g . min,(-1) 16 (+/-8.0) m in, and 0.12 (+/-0.11), respectively. Conclusions: The data suggest th at this analgesic method offers a simple and noninvasive route of admi nistration with a rapid increase of C-fen and a prolonged therapeutic fentanyl concentration. Future studies are required to determine the o ptimal liposome composition that would produce a sustained stable C-fe n within analgesic therapeutic concentrations.