Pharmacokinetics and safety of liposomal bupivacaine after local infiltration in healthy Chinese adults: a phase 1 study

Bernard My Cheung, Pauline Yeung Ng, Ying Liu, Manman Zhou, Vincent Yu, Julia Yang, Natalie Q Wang, Bernard My Cheung, Pauline Yeung Ng, Ying Liu, Manman Zhou, Vincent Yu, Julia Yang, Natalie Q Wang

Abstract

Background: Liposomal bupivacaine (LB) is a long-acting formulation of bupivacaine. The safety and efficacy of LB has been demonstrated across surgical procedures. However, pharmacokinetic (PK) parameters and safety of LB in the Chinese population have not been assessed.

Methods: In this single-arm, single center, phase 1, open-label study, PK and safety of local infiltration with LB 266 mg were assessed in healthy Chinese adults. Eligible participants were aged 18 to 55 years with biologic parents and grandparents of Chinese ethnicity, in generally good health (i.e., no clinically significant abnormalities), and with a body mass index (BMI) 19.0 to 24.0 kg/m2 (inclusive) and body weight ≥ 50 kg.

Results: Participants (N = 20) were predominantly men (80 %); mean age was 32 years; and mean BMI was 21.8 kg/m2. After LB administration, mean plasma levels of bupivacaine rapidly increased during the first hour and continued to increase through 24 h; plasma levels then gradually decreased through 108 h followed by a monoexponential decrease through 312 h. Geometric mean maximum plasma concentration was 170.9 ng/mL; the highest plasma bupivacaine concentration detected in any participant was 374.0 ng/mL. Twenty-two treatment-emergent adverse events were reported (mild, n = 21; moderate, n = 1).

Conclusions: After single-dose administration of LB, PK measures were similar to a previously reported profile in US adults. The highest observed peak plasma concentration of bupivacaine was several-fold below the plasma concentration threshold accepted as being associated with neurotoxicity or cardiotoxicity (2000-4000 ng/mL). These data support that LB is well tolerated and safe in individuals of Chinese descent.

Trial registration: NCT04158102 (ClinicalTrials.gov identifier), Date of registration: November 5, 2019.

Keywords: Analgesia; Anesthesia; Bridging; Pharmacology; Tolerability.

Conflict of interest statement

BMYC has nothing to disclose. PYN has nothing to disclose. YL and MZ are employees of Nuance Biotech (Shanghai) Co., Ltd. VY is an employee of Pacira BioSciences, Inc., and may hold stock or stock options. JY and NQW are former employees of Pacira BioSciences, Inc.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Mean plasma bupivacaine concentrations over time on (A) linear and (B) semilogarithmic scales. Error bars indicate standard deviation

References

    1. Garimella V, Cellini C. Postoperative pain control. Clin Colon Rectal Surg. 2013;26:191–6. doi: 10.1055/s-0033-1351138.
    1. American Society of Anesthesiologists Task Force on Acute Pain M Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116:248–73. doi: 10.1097/ALN.0b013e31823c1030.
    1. Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017;10:2287–98. doi: 10.2147/JPR.S144066.
    1. Rabbitts JA, Zhou C, Groenewald CB, Durkin L, Palermo TM. Trajectories of postsurgical pain in children: risk factors and impact of late pain recovery on long-term health outcomes after major surgery. Pain. 2015;156:2383–9. doi: 10.1097/j.pain.0000000000000281.
    1. Weiran L, Lei Z, Woo SM, Anliu T, Shumin X, Jing Z, et al. A study of patient experience and perception regarding postoperative pain management in Chinese hospitals. Patient Prefer Adherence. 2013;7:1157–62.
    1. Xiao H, Liu H, Liu J, Zuo Y, Liu L, Zhu H, et al. Pain prevalence and pain management in a Chinese hospital. Med Sci Monit. 2018;24:7809–19. doi: 10.12659/MSM.912273.
    1. Liu D, Ma J, Zhang Z, Yu A, Chen X, Feng C, et al. Management of postoperative pain in medical institutions in shandong province in China. Medicine (Baltimore) 2016;95:e2690. doi: 10.1097/MD.0000000000002690.
    1. Liu X, Luo C, Dai H, Fang W. Consumption trends and prescription patterns of opioids from 2011 to 2016: a survey in a Chinese city. BMJ Open. 2019;9:e021923. doi: 10.1136/bmjopen-2018-021923.
    1. Li RJ, Loyo Li M, Leon E, Ng CWK, Shindo M, Manzione K, et al. Comparison of opioid utilization patterns after major head and neck procedures between Hong Kong and the United States. JAMA Otolaryngol Head Neck Surg. 2018;144:1060–5. doi: 10.1001/jamaoto.2018.1787.
    1. Brummett CM, Waljee JF, Goesling J, Moser S, Lin P, Englesbe MJ, et al. New persistent opioid use after minor and major surgical procedures in US adults. JAMA Surg. 2017;152:e170504. doi: 10.1001/jamasurg.2017.0504.
    1. Jelting Y, Klein C, Harlander T, Eberhart L, Roewer N, Kranke P. Preventing nausea and vomiting in women undergoing regional anesthesia for cesarean section: challenges and solutions. Local Reg Anesth. 2017;10:83–90. doi: 10.2147/LRA.S111459.
    1. Fan L, Yu X, Zan P, Liu J, Ji T, Li G. Comparison of local infiltration analgesia with femoral nerve block for total knee arthroplasty: a prospective, randomized clinical trial. J Arthroplasty. 2016;31:1361–5. doi: 10.1016/j.arth.2015.12.028.
    1. Manna S, Wu Y, Wang Y, Koo B, Chen L, Petrochenko P, et al. Probing the mechanism of bupivacaine drug release from multivesicular liposomes. J Control Release. 2019;294:279–87. doi: 10.1016/j.jconrel.2018.12.029.
    1. Nedeljkovic SS, Kett A, Vallejo MC, Horn JL, Carvalho B, Bao X, et al. Transversus abdominis plane block with liposomal bupivacaine for pain after cesarean delivery in a multicenter, randomized, double-blind, controlled trial. Anesth Analg. 2020;131:1830–9. doi: 10.1213/ANE.0000000000005075.
    1. EXPAREL [package insert]. San Diego, CA: Pacira Pharmaceuticals Inc.; 2018.
    1. European Medicines Agency. EMEA/H/C/004586/2021 – Exparel liposomal: EPAR – Product information 2020. . Accessed April 22, 2021.
    1. Hutchins J, Vogel RI, Ghebre R, McNally A, Downs LS, Jr., Gryzmala E, et al. Ultrasound-guided subcostal transversus abdominis plane infiltration with liposomal bupivacaine for patients undergoing robotic-assisted hysterectomy: a retrospective study. Int J Gynecol Cancer. 2015;25:937–41. doi: 10.1097/IGC.0000000000000429.
    1. Hutchins JL, Renfro L, Orza F, Honl C, Navare S, Berg AA. The addition of intrathecal morphine to a transversus abdominis plane block with liposome bupivacaine provides more effective analgesia than transversus abdominis plane block with liposome bupivacaine alone: a retrospective study. Local Reg Anesth. 2019;12:7–13. doi: 10.2147/LRA.S190225.
    1. Amundson AW, Olsen DA, Smith HM, Torsher LC, Martin DP, Heimbach JK, et al. Acute Benefits after liposomal bupivacaine abdominal wall blockade for living liver donation: a retrospective review. Mayo Clin Proc Innov Qual Outcomes. 2018;2:186–93. doi: 10.1016/j.mayocpiqo.2018.03.003.
    1. Girone G, Do V, Cohen E, Deshpande R, Batra R. Utilization and impact of abdominal wall nerve blocks in living liver donors on post-operative outcomes. Am J Transplant. 2020;20:46–7.
    1. Hernandez MC, Panchamia J, Finnesgard EJ, Leiting JL, Franssen B, Saleem H, et al. Transversus abdominis plane blocks with liposomal bupivacaine after open major hepatectomy is associated with reduced early patient-reported pain scores and opioid administration. Surgery. 2018;164:1251–8. doi: 10.1016/j.surg.2018.07.023.
    1. Hutchins JL, Kesha R, Blanco F, Dunn T, Hochhalter R. Ultrasound-guided subcostal transversus abdominis plane blocks with liposomal bupivacaine vs. non-liposomal bupivacaine for postoperative pain control after laparoscopic hand-assisted donor nephrectomy: a prospective randomised observer-blinded study. Anaesthesia. 2016;71:930–7. doi: 10.1111/anae.13502.
    1. Fayezizadeh M, Majumder A, Neupane R, Elliott HL, Novitsky YW. Efficacy of transversus abdominis plane block with liposomal bupivacaine during open abdominal wall reconstruction. Am J Surg. 2016;212:399–405. doi: 10.1016/j.amjsurg.2015.12.026.
    1. Felling DR, Jackson MW, Ferraro J, Battaglia MA, Albright JJ, Wu J, et al. Liposomal bupivacaine transversus abdominis plane block versus epidural analgesia in a colon and rectal surgery enhanced recovery pathway: a randomized clinical trial. Dis Colon Rectum. 2018;61:1196–204. doi: 10.1097/DCR.0000000000001211.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Mustafa HJ, Wong HL, Al-Kofahi M, Schaefer M, Karanam A, Todd MM. Bupivacaine pharmacokinetics and breast milk excretion of liposomal bupivacaine administered after cesarean birth. Obstet Gynecol. 2020;136:70 – 6.
    1. Patel MA, Gadsden JC, Nedeljkovic SS, Bao X, Zeballos JL, Yu V, et al. Brachial plexus block with liposomal bupivacaine for shoulder surgery improves analgesia and reduces opioid consumption: results from a multicenter, randomized, double-blind, controlled trial. Pain Med. 2020;21:387–400.
    1. Johnson JA. Influence of race or ethnicity on pharmacokinetics of drugs. J Pharm Sci. 1997;86:1328-33.
    1. Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol. 2004;44:1083 – 105.
    1. Gantenbein M, Attolini L, Bruguerolle B, Villard PH, Puyoou F, Durand A, et al.Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A. Drug Metab Dispos. 2000;28:383-5.
    1. Ozdemir V, Kalow W, Tang BK, Paterson AD, Walker SE, Endrenyi L, et al. Evaluation of the genetic component of variability in CYP3A4 activity: a repeated drug administration method. Pharmacogenetics. 2000;10:373 – 88.
    1. Zhou Q, Yu X, Shu C, Cai Y, Gong W, Wang X, et al. Analysis of CYP3A4 genetic polymorphisms in Han Chinese. J Hum Genet. 2011;56:415 – 22.
    1. Rice D, Heil JW, Biernat L. Pharmacokinetic profile and tolerability of liposomal bupivacaine following a repeated dose via local subcutaneous infiltration in healthy volunteers. Clin Drug Investig. 2017;37:249 – 57.
    1. Chooi YC, Ding C, Magkos F. The epidemiology of obesity. Metabolism. 2019;92:6–10.
    1. Springer BD, Mason JB, Odum SM. Systemic Safety of Liposomal Bupivacaine in Simultaneous Bilateral Total Knee Arthroplasty. J Arthroplasty. 2018;33:97–101.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa