The Safety of EXPAREL^TM Bupivacaine Extended‐release Liposome Injection) Administered by Peripheral Nerve Block in Rabbits and Dogs

Abstract

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