title: Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers.
abstract: BACKGROUND
  Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia.
  
  
  OBJECTIVE
  The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers.
  
  
  METHODS
  Healthy adults were assigned to receive liposomal bupivacaine via subcutaneous infiltration in a single 266 mg dose (cohort 1) or in two 266 mg doses, with the second dose given immediately, 24, 48, or 72 h after the first dose (cohorts 2-5). Pharmacokinetic parameters were estimated from blood samples collected up to day 14. Subjects were monitored for adverse events and assessed for neurologic function, cardiac function, and infiltration area abnormalities.
  
  
  RESULTS
  Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (Cmax) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean Cmaxafter the second dose was higher, but always less than double the Cmaxfor cohort 1. The highest individual Cmax(589 ng/mL) was observed in a subject who received the second dose 24 h after the first dose (cohort 4), but was well below the reported thresholds for neurotoxicity and cardiac toxicity (2000 and 4000 ng/mL, respectively). A single and repeated dose were well-tolerated, and there were no clinically meaningful findings regarding neurologic examinations and electrocardiography.
  
  
  CONCLUSIONS
  The mean Cmaxfollowing a repeated dose of liposomal bupivacaine remained well below accepted values for central nervous system and cardiac toxicity. Liposomal bupivacaine was well-tolerated and revealed no clinically important safety signals. CLINICALTRIALS.
  NCT02210247.
authors.affiliation: Division of Surgery, Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit Number: 1489, Room Number: FCT19.6000, Houston, TX, 77030, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rice
authors.affiliation: Naval Medical Center San Diego, 200 W. Arbor Drive, San Diego, CA, 92103, USA.
authors.forename: Justin W
authors.initials: JW
authors.lastname: Heil
authors.affiliation: Medpace Clinical Pharmacology Unit, 5355 Medpace Way, Cincinnati, OH, 45227, USA. l.biernat@medpace.com.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Biernat
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002045:Bupivacaine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015331:Cohort Studies; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D002045:Bupivacaine