Pharmacokinetics and behavioral effects of liposomal hydromorphone suitable for perioperative use in rhesus macaques

Abstract

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 (MRT0-INF = 105.9 h) demonstrated extended-release pharmacokinetics compared to hydro when administered by either i.v. (MRT0-INF =1.1 h) or s.c. (MRT0-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.

Pharmacokinetics of ammonium sulfate gradient loaded liposome–encapsulated oxymorphone and hydromorphone in healthy dogs

“…Earlier studies in our laboratory have produced liposome‐encapsulated formulations of oxymorphone and hydromorphone that offer serum concentrations for 3–4 days, which may make them suitable for perioperative use in domestic and laboratory animals (Krugner‐Higby et al. , ; Smith et al. , ).…”

“…This method has been previously described by our laboratory (Krugner‐Higby et al. ). Briefly, a mixture of 80 μmol DPPC and 40 μmol cholesterol (Avanti Polar Lipids, AL, USA) was dried by removing chloroform, dissolved in 1 mL sterile tert‐butanol (Sigma Aldrich, MO, USA) by heating to 55 °C in a water bath, frozen in a dry ice‐isopropanol mixture, and lyophilized for 24 hours.…”

“…; Krugner‐Higby et al. ). These formulations were made using a freeze‐thaw method and liposome membranes composed of dipalmatoyl‐phosphatidylcholine (DPPC) and cholesterol.…”

Challenges with Assessing and Treating Pain in Research Primates: A Focused Survey and Literature Review

“…Many welfare frameworks and uni/multidimensional scales have been created to quantify pain and behaviour. For example, the Extended Welfare Assessment Grid (EWAG) for the assessment of welfare and cumulative suffering in experimental animals evaluates the following components: clinical condition, experimental/clinal events, environment, and behavioural deviations [ 72 ]. Having a grid with specific welfare descriptors aids in assessing objective behavioural measures.…”

“…Without sedation and/or training, primates may be unwilling to cooperate for a long duration. In primates, common opioids such as buprenorphine, hydromorphone, and tramadol have been administered through IV injection [ 51 , 72 , 101 ].…”