Safety and tolerability of DepoFoam^® encapsulated bupivacaine for epidural nerve block in rats and dogs

Abstract

Pacira Pharmaceuticals, Inc. is developing DepoBupivacaineTM (DB; bupivacaine extended‐release liposome injection) using multivesicular DepoFoam® technology for prolonged postoperative analgesia. The safety and tolerability of DB by epidural (ED) and "accidental" intrathecal (IT) routes were investigated. A sensitive silver stain method was used to evaluate the spinal cord. Gait abnormalities were recorded for up to 22 days, after dosing on day 1 in dogs. In rats, lethality was observed with bupivacaine solution (Bsol, 0.75 mg; 14/38) related to an exaggerated response to bupivacaine (BUP). No effects were seen with DB alone (1.5 mg). In dogs, limb impairment with Bsol (4/6, 15 mg) or DB (5/6, 45 mg) with 1.5% lidocaine/1:200,000 epinephrine was limited to day 1; no effects were seen with DB alone (45 mg; ED). With Bsol (15 mg), limb impairment was more frequent and longer lasting compared with DB (45 mg; IT). There was no histological evidence of damage to the spinal cord and adjacent tissues at the injection site. Depot effect was evidenced by 18% higher peak plasma concentration of BUP, despite threefold higher dose of DB vs. Bsol (45 vs. 15 mg). Data reported here are the first demonstration of the safety of DB after epidural administration in relevant toxicology species. Based on preclinical data, DB poses no risk beyond that of Bsol.Research support was provided by Pacira Pharmaceuticals, Inc.