title: High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans.
abstract: BACKGROUND
  Depot formulations prolong the analgesic effect of local anesthetics and reduce peak plasma drug concentration. This allows for safer administration of larger doses of local anesthetics, which further prolongs the duration of analgesic effect. We previously reported the development of large multivesicular vesicles (LMVVs) remotely loaded with bupivacaine (LMVV liposomal bupivacaine) and demonstrated a >5-fold prolongation of analgesic effect in animals and humans. In this study, we present pharmacokinetic data of LMVV liposomal bupivacaine in humans.
  
  
  METHODS
  Healthy volunteers received subcutaneous injections of 20 mL plain 0.5% bupivacaine and, 1 week later, 20 mL of 2% LMVV liposomal bupivacaine in a prospective, open-label, crossover, controlled study.
  
  
  RESULTS
  Eight subjects were studied. No subjective side effects of local anesthetics were observed. The maximal plasma concentration and the time to achieve maximal plasma concentration were assessed by modeling plasma concentration-time profiles. Maximal plasma concentration was not significantly different between groups (0.87 +/- 0.45 microg/mL and 0.83 +/- 0.34 microg/mL for plain and liposomal bupivacaine, respectively; P = not significant, 0.83). These values are well below the putative toxic plasma concentration of 2 to 4 microg/mL. Time to achieve maximal plasma concentration was 7-fold greater for the liposomal preparation (262 +/- 149 minutes vs 37.5 +/- 16 minutes, P < 0.01).
  
  
  CONCLUSIONS
  Peak plasma bupivacaine concentrations were not different in the 2 groups, despite a 4-fold increase in total bupivacaine dose administered in the novel liposomal preparation. The delayed elimination and prolonged redistribution of liposomal bupivacaine to plasma is compatible with the depot-related slow-release effect leading to the prolonged pharmacodynamic effect previously reported.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. edavidson@hadassah.org.il
authors.forename: Elyad M
authors.initials: EM
authors.lastname: Davidson
authors.forename: Yechezkel
authors.initials: Y
authors.lastname: Barenholz
authors.forename: Rivka
authors.initials: R
authors.lastname: Cohen
authors.forename: Simon
authors.initials: S
authors.lastname: Haroutiunian
authors.forename: Leonid
authors.initials: L
authors.lastname: Kagan
authors.forename: Yehuda
authors.initials: Y
authors.lastname: Ginosar
mesh_terms: D000328:Adult; D000779:Anesthetics, Local / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002045:Bupivacaine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D005260:Female; D006207:Half-Life; D006801:Humans; D007279:Injections, Subcutaneous; D008081:Liposomes; D008297:Male; D011446:Prospective Studies
chemical_list: D000779:Anesthetics, Local; D003692:Delayed-Action Preparations; D008081:Liposomes; D002045:Bupivacaine