The safety and tolerability evaluation of DepoFoam bupivacaine (bupivacaine extended-release liposome injection) administered by incision wound infiltration in rabbits and dogs

Abstract

Objective: DepoFoam bupivacaine (DB) is in development for prolonged postoperative analgesia. Studies were conducted to evaluate the potential local and systemic toxicity and any effect on wound healing after wound infiltration.

Methods: The model simulates an inguinal hernia (skin incision ∼2.5 and 5.5 cm). Animals (four/sex/group of each species) received DB 9, 18 or either 25 or 30 mg/kg, bupivacaine solution (B_sol; 7.5 mg/ml, 9 mg/kg) or saline. DB was given at 0.6, 1.2 and 1.0 or 1.2 ml/kg, respectively, and B_sol or saline at 1.2 ml/kg. Each dose was infiltrated in small fractions on Day 1. End points included histology on Days 3 and 15. Wound healing was recorded on Day 2 through Day 15.

Results: There was no adverse effect in either species. Notably, granulomatous inflammation was noted in surgical sites from 8 of 24 rabbits in the DB groups only. Based on the minimal to mild severity on Day 15, this was considered a normal reaction against the liposomes. Except for granulomatous inflammation, there were no differences in overall incidence or severity of histologic changes in the sites dosed to DB, saline or B_sol.

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

Keywords:

• bupivacaine
• hernia repair
• liposomes
• pharmacokinetics
• sustained release
• wound infiltration

Acknowledgments

The authors wish to thank D Rickert for the statistical analyses of the pharmacokinetic data. Abstract presented at: Annual Winter Meeting of the British Pharmacological Society, Brighton, UK, 16 December 2008.