Pharmacokinetics and Safety of INL-001 (Bupivacaine HCl) Implants Compared with Bupivacaine HCl Infiltration After Open Unilateral Inguinal Hernioplasty

David Leiman, Gwendolyn Niebler, Harold S Minkowitz, David Leiman, Gwendolyn Niebler, Harold S Minkowitz

Abstract

Introduction: Surgical site infiltration with bupivacaine HCl results in short-lived analgesia for postsurgical pain and carries the risk of systemic bupivacaine toxicity due to accidental intravascular injection. INL-001 is a bupivacaine HCl collagen-matrix implant that provides extended delivery of bupivacaine directly at the site and avoids the risk of accidental injection. Here, we examine the pharmacokinetic (PK) and safety profile of INL-001 placement during unilateral open inguinal hernioplasty.

Methods: This multicenter, single-blind study (NCT03234374) enrolled patients undergoing open inguinal hernioplasty to receive three INL-001 implants, each containing 100 mg bupivacaine HCl (n = 34) or local infiltration of 0.25% bupivacaine HCl 175 mg (n = 16). Acetaminophen was provided in the postsurgical period and supplemented by opioids for breakthrough pain, as needed. PK blood samples were taken before surgery and up to 96 h after drug administration.

Results: INL-001 demonstrated a prolonged rate of absorption and clearance of bupivacaine compared with 0.25% bupivacaine HCl 175 mg, as demonstrated by a longer time to peak plasma concentration and terminal elimination half-life. Peak plasma concentration with INL-001 300 mg was comparable to bupivacaine HCl 175 mg and well below levels associated with systemic bupivacaine toxicity. The most common adverse events (AEs) in both groups were associated with general anesthesia and the postsurgical setting. No AE was related to the implant, including those associated with wound healing.

Conclusions: These findings demonstrate that INL-001 provides immediate and extended delivery of bupivacaine and is well tolerated in patients undergoing open inguinal hernioplasty with no adverse effect on wound healing.

Trial registration: Clinicaltrials.gov identifier, NCT03234374.

Keywords: Bupivacaine HCl; Collagen-matrix implant; INL-001; Postsurgical pain; Xaracoll.

Figures

Fig. 1
Fig. 1
Study flow diagram. HCl hydrochloride, PK pharmacokinetic. Asterisk: Randomized population = all patients who received a randomization number, regardless of whether they received the study drug. Dagger: Patients were considered randomized, but not enrolled or treated if the investigator encountered a condition during surgery which prevented placement of an implant. Double dagger: Safety population = all patients who received INL-001 bupivacaine HCl collagen-matrix implant or 0.25% bupivacaine HCl infiltration. Section sign: PK population = all patients who received study drug and had ≥ 1 postimplantation/infiltration blood sample obtained. Double verticle line: Per-protocol PK population = all patients in the PK population with no major PK-related protocol deviations and who had sufficient data to calculate
Fig. 2
Fig. 2
Mean (± SD) plasma bupivacaine concentrations by treatment on semi-logarithmic scale (PK population). a Expanded initial postsurgical period of 0 to 6 h. b Full period of PK measurements from 0 to 96 h postsurgery. Note: If the actual sampling time (measured from dosing) was outside of the collection window for nominal time points, the corresponding concentration was excluded from concentration vs. time descriptive summaries and plots but was still used in the calculation of PK parameters. The lower limit of quantitation for bupivacaine was 1 ng/mL. HCl hydrochloride, PK pharmacokinetic, SD standard deviation

References

    1. Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017;10:2287–2298. doi: 10.2147/JPR.S144066.
    1. Song D, Greilich NB, White PF, Watcha MF, Tongier WK. Recovery profiles and costs of anesthesia for outpatient unilateral inguinal herniorrhaphy. Anesth Analg. 2000;91(4):876–881. doi: 10.1097/00000539-200010000-00020.
    1. Andresen K, Rosenberg J. Management of chronic pain after hernia repair. J Pain Res. 2018;11:675–681. doi: 10.2147/JPR.S127820.
    1. Chou R, Deyo R, Devine B, et al. The effectiveness and risks of long-term opioid treatment of chronic pain. Evid Rep Technol Assess (Full Rep). 2014;218:1–219.
    1. Chou R, Gordon DB, de Leon-Casasola OA, et al. Guidelines on the management of postoperative pain. J Pain. 2016;17(2):131–157. doi: 10.1016/j.jpain.2015.12.008.
    1. Gadsden J. Local anesthetics: Clinical pharmacology and rational selection. In: Hadzic A, editors. Carrera A, Clark TB, Gadsden J, et al, associate editors. Hadzic’s Peripheral nerve blocks and anatomy for ultrasound-guided regional anesthesia. 2nd ed. McGraw-Hill; 2012. pp. 29–40.
    1. Gupta A. Wound infiltration with local anaesthetics in ambulatory surgery. Curr Opin Anaesthesiol. 2010;23(6):708–713. doi: 10.1097/ACO.0b013e32833f0dd7.
    1. Gitman M, Fettiplace M, Weinberg G. Toxicity of local anesthetics. . Accessed 09 Sep 2020.
    1. US Food and Drug Administration (FDA). FDA briefing document: Anesthetic and Analgesic Drug Products Advisory Committee meeting. February 14–15, 2018; Silver Spring, MD, USA.
    1. Knudsen K, Beckman Suurküla M, Blomberg S, Sjövall J, Edvardsson N. Central nervous and cardiovascular effects of I.V. infusions of ropivacaine, bupivacaine and placebo in volunteers. Br J Anaesth. 1997;78(5):507–514. doi: 10.1093/bja/78.5.507.
    1. Leone S, Di Cianni S, Casati A, Fanelli G. Pharmacology, toxicology, and clinical use of new long acting local anesthetics, ropivacaine and levobupivacaine. Acta Biomed. 2008;79(2):92–105.
    1. Nanji KC, Patel A, Shaikh S, Seger DL, Bates DW. Evaluation of perioperative medication errors and adverse drug events. Anesthesiology. 2016;124(1):25–34. doi: 10.1097/ALN.0000000000000904.
    1. Velanovich V, Rider P, Deck K, et al. Safety and efficacy of bupivacaine HCl collagen-matrix implant (INL-001) in open inguinal hernia repair: results from two randomized controlled trials. Adv Ther. 2019;36(1):200–216. doi: 10.1007/s12325-018-0836-4.
    1. Xaracoll® (bupivacaine hydrochloride) implant [package insert]. Athlone, Ireland: Innocoll Pharmaceuticals Limited. 2020. . Accessed 8 Sep 2020.
    1. Franneby U, Sandblom G, Nyren O, Nordin P, Gunnarsson U. Self-reported adverse events after groin hernia repair, a study based on a national register. Value Health. 2008;11(5):927–932. doi: 10.1111/j.1524-4733.2008.00330.x.
    1. Kerr DR, Kohan L. Local infiltration analgesia: a technique for the control of acute postoperative pain following knee and hip surgery: a case study of 325 patients. Acta Orthop. 2008;79(2):174–183. doi: 10.1080/17453670710014950.
    1. Cusack SL, Minkowitz HS, Kuss M, Jaros M, Hemsen L. A randomized, multicenter, pilot study comparing the efficacy and safety of a bupivacaine-collagen implant (Xaracoll®) with the ON-Q PainBuster® Post-op Pain Relief System following open gynecological surgery. J Pain Res. 2012;5:453–461. doi: 10.2147/JPR.S37310.
    1. Cusack SL, Reginald P, Hemsen L, Umerah E. The pharmacokinetics and safety of an intraoperative bupivacaine-collagen implant (Xaracoll®) for postoperative analgesia in women following total abdominal hysterectomy. J Pain Res. 2013;6:151–159. doi: 10.2147/JPR.S40976.
    1. Cusack SL, Jaros M, Kuss M, Minkowitz HS, Winkle P, Hemsen L. Clinical evaluation of Xaracoll®, a bupivacaine-collagen implant, for postoperative analgesia in two multicenter, randomized, double-blind, placebo-controlled pilot studies. J Pain Res. 2012;5:217–225. doi: 10.2147/JPR.S33453.
    1. Leiman D, Niebler G, Minkowitz H, editors. Pharmacokinetics and safety of the bupivacaine collagen-matrix implant (INL-001) compared to liquid bupivacaine infiltration after open inguinal hernia repair. World Congress on Regional Anesthesia & Pain Medicine; April 19–21, 2018; New York, NY, USA. Abstract 5445.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi