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Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers



Liposomal bupivacaine is indicated for administration into the surgical site to produce post-surgical analgesia.


The objectives of this study were to characterize the pharmacokinetic and safety profiles of liposomal bupivacaine following a repeated dose in healthy volunteers.


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.


Twelve subjects were assigned to each cohort. The mean ± standard deviation maximum observed plasma concentration (C max) of bupivacaine after a single dose was 129 ± 47 ng/mL. The mean C max after the second dose was higher, but always less than double the C max for cohort 1. The highest individual C max (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.


The mean C max following 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. Identifier


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  1. 1.

    Exparel [prescribing information]. Parsippany, NJ: Pacira Pharmaceuticals, Inc.; 2015.

  2. 2.

    Hu D, Onel E, Singla N, Kramer WG, Hadzic A. Pharmacokinetic profile of liposome bupivacaine injection following a single administration at the surgical site. Clin Drug Investig. 2013;33:109–15.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Bramlett K, Onel E, Viscusi ER, Jones K. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee. 2012;19:530–6.

    Article  PubMed  Google Scholar 

  4. 4.

    Richard BM, Rickert DE, Newton PE, Ott LR, Haan D, Brubaker AN, et al. Safety evaluation of EXPAREL (DepoFoam bupivacaine) administered by repeated subcutaneous injection in rabbits and dogs: species comparison. J Drug Deliv. 2011;2011:467429.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Joshi GP, Cushner FD, Barrington JW, Lombardi AV Jr, Long WJ, Springer BD, et al. Techniques for periarticular infiltration with liposomal bupivacaine for the management of pain after hip and knee arthroplasty: a consensus recommendation. J Surg Orthop Adv. 2015;24:27–35.

    Article  PubMed  Google Scholar 

  6. 6.

    Hadzic A, Minkowitz HS, Melson TI, Berkowitz R, Uskova A, Ringold F, et al. Liposome bupivacaine femoral nerve block for postsurgical analgesia after total knee arthroplasty. Anesthesiology. 2016;124:1372–83.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    International Conference on Harmonisation Working Group. ICH harmonised tripartite guideline: guideline for good clinical practice E6 (R1). In: International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use; June 10, 1996; Washington, DC. Accessed 13 Sept 2016.

  8. 8.

    Guidance for industry: bioanalytical method validation; 2001. Accessed 10 Nov 2016.

  9. 9.

    European Medicines Agency. Guideline on bioanalytical method validation; 2011. Accessed 13 Jan 2017.

  10. 10.

    Bardsley H, Gristwood R, Baker H, Watson N, Nimmo W. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol. 1998;46:245–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Jorfeldt L, Lofstrom B, Pernow B, Persson B, Wahren J, Widman B. The effect of local anaesthetics on the central circulation and respiration in man and dog. Acta Anaesthesiol Scand. 1968;12:153–69.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Connolly C, Coventry DM, Wildsmith JA. Double-blind comparison of ropivacaine 7.5 mg ml−1 with bupivacaine 5 mg ml−1 for sciatic nerve block. Br J Anaesth. 2001;86:674–7.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Viscusi ER, Candiotti KA, Onel E, Morren M, Ludbrook GL. The pharmacokinetics and pharmacodynamics of liposome bupivacaine administered via a single epidural injection to healthy volunteers. Reg Anesth Pain Med. 2012;37:616–22.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Knudsen K, Beckman Suurkula M, Blomberg S, Sjovall J, Edvardsson N. Central nervous and cardiovascular effects of i.v. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth. 1997;78:507–14.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Scott DB, Lee A, Fagan D, Bowler GM, Bloomfield P, Lundh R. Acute toxicity of ropivacaine compared with that of bupivacaine. Anesth Analg. 1989;69:563–9.

    CAS  PubMed  Google Scholar 

  16. 16.

    Covino BG, Wildsmith JA. Clinical pharmacology of local anesthetic agents. In: Cousins MJ, Bridenbaugh PO, editors. Neural blockade in clinical anesthesia and management of pain. 3rd ed. Philadelphia, PA: Lippincott-Raven; 1998. p. 97–128.

    Google Scholar 

  17. 17.

    Neal JM, Bernards CM, Butterworth JF, Di Gregorio G, Drasner K, Hejtmanek MR, et al. ASRA practice advisory on local anesthetic systemic toxicity. Reg Anesth Pain Med. 2010;35:152–61.

    Article  PubMed  Google Scholar 

  18. 18.

    Veering BT, Burm AG, Feyen HM, Olieman W, Souverijn JHM, Van Kleef JW. Pharmacokinetics of bupivacaine during postoperative epidural infusion: enantioselectivity and role of protein binding. Anesthesiology. 2002;96:1062–9.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Bergese SD, Onel E, Morren M, Morganroth J. Bupivacaine extended-release liposome injection exhibits a favorable cardiac safety profile. Reg Anesth Pain Med. 2012;37:145–51.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Mather LE, McCall P, McNicol PL. Bupivacaine enantiomer pharmacokinetics after intercostal neural blockade in liver transplantation patients. Anesth Analg. 1995;80:328–35.

    CAS  PubMed  Google Scholar 

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Editorial and medical writing assistance was provided by Michael D. Morren, RPh, MBA, of Peloton Advantage, LLC, supported by Pacira Pharmaceuticals, Inc., the manufacturer of liposomal bupivacaine. The authors were fully responsible for the content, editorial decisions, and opinions expressed in the current article. The authors did not receive an honorarium related to the development of this manuscript.

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Corresponding author

Correspondence to Lukasz Biernat.

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Conflicts of interest

D. Rice was a consultant for Pacira Pharmaceuticals, Inc. J. W. Heil has no conflicts of interest to disclose. L. Biernat is employed by Medpace Clinical Pharmacology Unit, the institution contracted to conduct the study, supported by Pacira Pharmaceuticals, Inc.

Source of funding

This study was funded by Pacira Pharmaceuticals, Inc.

Ethical approval/informed consent

The study was approved by an independent ethics committee (Western Institutional Review Board, Puyallup, WA, USA), and all participants provided written informed consent before any study procedures were performed. The study was conducted from August to September 2014 in accordance with guidelines established by the International Council for Harmonisation for Good Clinical Practice [7] and the Declaration of Helsinki.

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Rice, D., Heil, J.W. & Biernat, L. Pharmacokinetic Profile and Tolerability of Liposomal Bupivacaine Following a Repeated Dose via Local Subcutaneous Infiltration in Healthy Volunteers. Clin Drug Investig 37, 249–257 (2017).

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  • Bupivacaine
  • Inguinal Hernia Repair
  • Repeated Dose
  • Central Nervous System Toxicity
  • Wound Infiltration