title: A model to evaluate the pharmacokinetic and pharmacodynamic variables of extended-release products using in vivo tissue microdialysis in humans: bupivacaine-loaded microcapsules.
abstract: Biodegradable microcapsules produce an ultra-long duration of local anesthesia. We hypothesized that this duration is caused by the sustained-release of bupivacaine from the microcapsules into the surrounding tissue. Previous studies investigated the pharmacokinetics (PKs) of bupivacaine after release from microcapsules and absorption into the systemic circulation. Microdialysis sampling can determine the PKs of any drug at its site of injection. This study was performed to characterize the PKs of bupivacaine and dexamethasone released from microcapsules at a subcutaneous injection site over a 96-h period in volunteers. Bupivacaine concentrations were compared with clinical variables of local anesthetic blockade. This study demonstrates that bupivacaine is released in a sustained manner from microcapsules, that bupivacaine concentrations increase for 24-34 h after microcapsule injection, and that analgesia parallels the tissue bupivacaine concentration obtained by microdialysis. Analgesia was equally rapid in onset with aqueous and microcapsule bupivacaine (P = 0.23). Analgesia was still present at 78% of microcapsule-injected sites after 96 h, significantly longer than for aqueous bupivacaine (P < 0.001). Mild pruritus was the most common side effect, occurring with 56% of the microcapsule injections. Dexamethasone-containing bupivacaine microcapsules are well tolerated and produce a prolonged duration of skin analgesia. Systemic absorption of bupivacaine produces higher peak plasma levels after aqueous injection than after microcapsule injection, despite the injection of a threefold larger load of bupivacaine in the latter.
  
  
  CONCLUSIONS
  Microcapsules loaded with bupivacaine and dexamethasone and administered by subcutaneous injection produce prolonged cutaneous anesthesia and analgesia. Determination of local tissue pharmacokinetic variables of bupivacaine by microdialysis confirms that the prolonged duration of anesthesia is caused by the extended release characteristics of the microcapsules.
authors.affiliation: Department of Anesthesiology, Virginia Mason Clinic, Seattle, Washington 98111, USA. anedjk@vmmc.org
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Kopacz
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Bernards
authors.forename: Hugh W
authors.initials: HW
authors.lastname: Allen
authors.forename: Craig
authors.initials: C
authors.lastname: Landau
authors.forename: Partha
authors.initials: P
authors.lastname: Nandy
authors.forename: Danlin
authors.initials: D
authors.lastname: Wu
authors.forename: Peter G
authors.initials: PG
authors.lastname: Lacouture
mesh_terms: D000328:Adult; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D002045:Bupivacaine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002214:Capsules; D003692:Delayed-Action Preparations; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006358:Hot Temperature; D006801:Humans; D008297:Male; D017551:Microdialysis; D008954:Models, Biological; D010147:Pain Measurement / Q000187:drug effects
chemical_list: D000779:Anesthetics, Local; D000893:Anti-Inflammatory Agents; D002214:Capsules; D003692:Delayed-Action Preparations; D003907:Dexamethasone; D002045:Bupivacaine