A sustained-release DepoFoam injection formulation of bupivacaine (EXPAREL, 15 mg/mL) is currently being investigated for postsurgical analgesia via peripheral nerve block (PNB). Single-dose toxicology studies of EXPAREL (9, 18, and 30 mg/kg), bupivacaine solution (Bsol, 9 mg/kg), and saline injected around the brachial plexus nerve bundle were performed in rabbits and dogs. The endpoints included clinical pathology, pharmacokinetics, and histopathology evaluation on Day 3 and Day 15 (2/sex/group/period). EXPAREL resulted in a nearly 4-fold lower C max versus Bsol at the same dose. EXPAREL was well tolerated at doses up to 30 mg/kg. The only EXPAREL-related effect seen was minimal to mild granulomatous inflammation of adipose tissue around nerve roots (8 of 24 rabbits and 7 of 24 dogs) in the brachial plexus sites. The results indicate that EXPAREL was well tolerated in these models and did not produce nerve damage after PNB in rabbits and dogs.

EXPAREL (bupivacaine extended-release liposome injection), DepoFoam bupivacaine, is in development for prolonged postsurgical analgesia. Repeat-dose toxicity studies were conducted in rabbits and dogs to compare the potential local and systemic toxicities of EXPAREL and bupivacaine HCl (Bsol), and the reversibility of any effects. Dogs tolerated much larger doses than rabbits. EXPAREL-related minimal-to-moderate granulomatous inflammation was noted at the injection sites. In recovery animals, the granulomatous inflammation was observed less frequently and was characterized by an increased number of multinucleated giant cells. These effects were considered a normal response to liposomes and nonadverse. Rabbits are more sensitive than dogs. In rabbits, convulsions were noted with EXPAREL and more frequently with Bsol; a NOAEL was not identified. In dogs, EXPAREL was well tolerated (NOAEL > 30 mg/kg/dose). The cumulative exposure of EXPAREL in these studies is well in excess of the proposed maximum single-dose exposure that is intended in humans.

The data reported here are the first demonstration of the safety of DB in toxicology species.

Bupivacaine solutions have been used for many years by multiple routes with peripheral nerve block (PNB) becoming increasingly popular. A sustained‐release DepoFoam® injection formulation of bupivacaine (EXPAREL, EXP, 15 mg/mL) is currently being investigated for post‐surgical analgesia via PNB. The program focused on showing that this novel formulation is well tolerated and did not produce nerve damage after PNB in rabbits and dogs. The single‐dose toxicology studies of EXP (9, 18, and 30 mg/kg), bupivacaine HCL solution (Bsol, 9 mg/kg) and saline control included clinical pathology, toxicokinetics, organ weight and full histopathology evaluation on Day 3 and Day 15 (2/sex/group/period). The administration of EXP resulted in 2‐ to 3‐fold lower Cmax than Bsol. EXP was well tolerated at doses up to 30 mg/kg. There was no evidence of nerve damage after PNB. The only EXP‐related effect seen was minimal to mild granulomatous inflammation of adipose tissue around nerve roots (7‐8 of 24 animals), in the brachial plexus sites; this low severity effect was considered an expected response to the liposomes, and non adverse. Based on these studies, EXP has a low potential for producing adverse local or systemic effects when given as a single dose. These preclinical toxicology data support the first‐time‐inhuman trial of EXP by this route.Source of Research Support: Pacira Pharmaceuticals, Inc

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.