title: The safety of liposome bupivacaine following various routes of administration in animals.
abstract: BACKGROUND
  This report presents results from four preclinical studies evaluating safety and pharmacokinetics (PKs) of liposome bupivacaine following intravascular (intravenous [IV], intra-arterial [IA]), epidural, and intrathecal administration in dogs.
  
  
  METHODS
  Intravascular administration was initially tested in a pilot study to determine maximum tolerated doses, and then in an expanded study of systemic adverse effects and PKs. An epidural study compared properties of liposome bupivacaine alone and in combination with lidocaine/epinephrine vs bupivacaine HCl. Another study assessed effects after intrathecal administration.
  
  
  RESULTS
  In the initial intravascular studies, maximum doses at which no meaningful adverse events were observed with liposome bupivacaine were higher than for bupivacaine HCl (4.5 mg/kg IV vs 0.75 mg/kg IV, and 1.5 mg/kg IA vs 0.1 mg/kg IA, respectively). In the expanded intravascular study, there was no mortality or changes in pathology; adverse clinical signs included convulsions, lying on side, and decreased muscle tone (all were transient). In the epidural study, liposome bupivacaine was well tolerated at doses up to the highest dose tested (40 mg), with no evidence of spinal cord damage and with less motor blockade than bupivacaine HCl 15 mg. Intrathecal administration of liposome bupivacaine 40 mg was not associated with meaningful safety concerns and resulted in less motor blockade than bupivacaine HCl 15 mg. PK analyses showed that maximum plasma bupivacaine levels following administration of liposome bupivacaine (4.5 mg/kg IV and 40 mg epidural) were similar to maximum plasma bupivacaine levels following a threefold lower dose of bupivacaine HCl (1.5 mg/kg IV and 15 mg epidural).
  
  
  CONCLUSIONS
  Liposome bupivacaine has a favorable safety profile compared with bupivacaine HCl when administered to dogs via intravascular, epidural, and intrathecal routes. This favorable safety profile is likely related to the liposome-bound nature of bupivacaine in the liposome bupivacaine formulation.
authors.affiliation: Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical School, Dallas, TX, USA.
authors.forename: Girish P
authors.initials: GP
authors.lastname: Joshi
authors.affiliation: Pacira Pharmaceuticals, Inc., Parsippany, NJ, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Patou
authors.affiliation: Pacira Pharmaceuticals, Inc., Parsippany, NJ, USA.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kharitonov
keywords: bupivacaine; drug administration routes; local anesthesia; spinal injections