Pharmacokinetics and Behavioral Effects of Liposomal Hydromorphone Suitable for Perioperative Use in Rhesus Macaques

Introduction: This study aims to evaluate the pharmacokinetic, behavioral, and motor effects of a liposomal preparation of hydromorphone hydrochloride (LE-hydro) in rhesus monkeys. We administered either 2 mg/kg of LE-hydro (n = 8) subcutaneous (s.c.) or 0.1 mg/kg of standard pharmaceutical hydromorphone HCl (hydro) preparation either intravenous (i.v.; n = 4) or s.c. (n = 5).

Materials And Methods: Serial blood samples were drawn after injection and analyzed for serum hydro concentration by liquid chromatography/mass spectrometry. Following s.c. injection of 0.1 mg/kg hydro or 2 mg/kg LE-hydro, behavioral evaluations were conducted in groups of rhesus monkeys (n = 10/group) in the presence of a compatible stimulus animal and motor skills were also evaluated (n = 10/group). The motor skills test consisted of removing a food reward (carrot ring) from either a straight peg (simple task) or a curved peg (difficult task).

Results: LE-hydro (MRT(0-INF) = 105.9 h) demonstrated extended-release pharmacokinetics compared to hydro when administered by either i.v. (MRT(0-INF) =1.1 h) or s.c. (MRT(0-INF) =1.3 h) routes. Hydro did not affect motor performance of the simpler task, but the monkeys' performance deteriorated on the more difficult task at 0.5 and 1 h after injection. LE-hydro had no effect on motor skills in either the simpler or more difficult task.

Conclusions: The results of these studies indicate that LE-hydro has a pharmacokinetic and behavioral side effects profile consistent with an analgesic that could be tested for surgical use in animals. Our studies also expand the use of rhesus monkeys as a translational behavioral pharmacodynamics model for testing extended-release opioid medication.