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

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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.

Electronic supplementary material

The online version of this article (10.1007/s12325-020-01565-x) contains supplementary material, which is available to authorized users.

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Most cited references 15

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Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council.

Roger Chou, Debra B Gordon, Oscar A de Leon-Casasola … (2016)

Most patients who undergo surgical procedures experience acute postoperative pain, but evidence suggests that less than half report adequate postoperative pain relief. Many preoperative, intraoperative, and postoperative interventions and management strategies are available for reducing and managing postoperative pain. The American Pain Society, with input from the American Society of Anesthesiologists, commissioned an interdisciplinary expert panel to develop a clinical practice guideline to promote evidence-based, effective, and safer postoperative pain management in children and adults. The guideline was subsequently approved by the American Society for Regional Anesthesia. As part of the guideline development process, a systematic review was commissioned on various aspects related to various interventions and management strategies for postoperative pain. After a review of the evidence, the expert panel formulated recommendations that addressed various aspects of postoperative pain management, including preoperative education, perioperative pain management planning, use of different pharmacological and nonpharmacological modalities, organizational policies, and transition to outpatient care. The recommendations are based on the underlying premise that optimal management begins in the preoperative period with an assessment of the patient and development of a plan of care tailored to the individual and the surgical procedure involved. The panel found that evidence supports the use of multimodal regimens in many situations, although the exact components of effective multimodal care will vary depending on the patient, setting, and surgical procedure. Although these guidelines are based on a systematic review of the evidence on management of postoperative pain, the panel identified numerous research gaps. Of 32 recommendations, 4 were assessed as being supported by high-quality evidence, and 11 (in the areas of patient education and perioperative planning, patient assessment, organizational structures and policies, and transitioning to outpatient care) were made on the basis of low-quality evidence.

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Poorly controlled postoperative pain: prevalence, consequences, and prevention

Tong Gan (2017)

This review provides an overview of the clinical issue of poorly controlled postoperative pain and therapeutic approaches that may help to address this common unresolved health-care challenge. Postoperative pain is not adequately managed in greater than 80% of patients in the US, although rates vary depending on such factors as type of surgery performed, analgesic/anesthetic intervention used, and time elapsed after surgery. Poorly controlled acute postoperative pain is associated with increased morbidity, functional and quality-of-life impairment, delayed recovery time, prolonged duration of opioid use, and higher health-care costs. In addition, the presence and intensity of acute pain during or after surgery is predictive of the development of chronic pain. More effective analgesic/anesthetic measures in the perioperative period are needed to prevent the progression to persistent pain. Although clinical findings are inconsistent, some studies of local anesthetics and nonopioid analgesics have suggested potential benefits as preventive interventions. Conventional opioids remain the standard of care for the management of acute postoperative pain; however, the risk of opioid-related adverse events can limit optimal dosing for analgesia, leading to poorly controlled acute postoperative pain. Several new opioids have been developed that modulate μ-receptor activity by selectively engaging intracellular pathways associated with analgesia and not those associated with adverse events, creating a wider therapeutic window than unselective conventional opioids. In clinical studies, oliceridine (TRV130), a novel μ-receptor G-protein pathway-selective modulator, produced rapid postoperative analgesia with reduced prevalence of adverse events versus morphine.

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Local infiltration analgesia: a technique for the control of acute postoperative pain following knee and hip surgery: a case study of 325 patients.

Dennis Kerr, Lawrence Kohan (2008)

We have developed a multimodal technique for the control of pain following knee and hip surgery, called "local infiltration analgesia" (LIA). It is based on systematic infiltration of a mixture of ropiva-caine, ketorolac, and adrenaline into the tissues around the surgical field to achieve satisfactory pain control with little physiological disturbance. The technique allows virtually immediate mobilization and earlier discharge from hospital. In this open, nonrandomized case series, we used LIA to manage postoperative pain in all 325 patients presenting to our service from Jan 1, 2005 to Dec 31,2006 for elective hip resurfacing (HRA), primary total hip replacement (THR), or primary total knee replacement arthroplasty (TKR). We recorded pain scores, mobilization times, and morphine usage for the entire group. Pain control was generally satisfactory (numerical rating scale pain score range 0-3). No morphine was required for postoperative pain control in two-thirds of the patients. Most patients were able to walk with assistance between 5 and 6 h after surgery and independent mobility was achieved 13-22 h after surgery. Orthostatic hypotension, nausea, and vomiting were occasionally associated with standing for the first time, but other side effects were unremarkable. 230 (71%) of the 325 patients were discharged directly home after a single overnight stay in hospital. Local infiltration analgesia is simple, practical, safe, and effective for pain management after knee and hip surgery.

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Author and article information

Contributors

David Leiman: leimanmd@gmail.com

Journal

Journal ID (nlm-ta): Adv Ther

Journal ID (iso-abbrev): Adv Ther

Title: Advances in Therapy

Publisher: Springer Healthcare (Cheshire )

ISSN (Print): 0741-238X

ISSN (Electronic): 1865-8652

Publication date (Electronic): 25 November 2020

Publication date PMC-release: 25 November 2020

Publication date (Print): 2021

Volume: 38

Issue: 1

Pages: 691-706

Affiliations

[1 ]HD Research LLC, Houston, TX USA

[2 ]GRID grid.267308.8, ISNI 0000 0000 9206 2401, University of Texas Health Science Center, ; Houston, TX USA

[3 ]Innocoll Inc, Newtown Square, PA USA

Article

Publisher ID: 1565

DOI: 10.1007/s12325-020-01565-x

PMC ID: 7854444

PubMed ID: 33237534

SO-VID: 5c3045b4-e847-4985-9a1d-34c20037cee3

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date received : 22 September 2020

Date accepted : 7 November 2020

Funding

Funded by: Innocoll Inc.

Custom metadata

Keywords: bupivacaine hcl,collagen-matrix implant,inl-001,postsurgical pain,xaracoll

Data availability:

Keywords: bupivacaine hcl, collagen-matrix implant, inl-001, postsurgical pain, xaracoll

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

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Abstract

Introduction

Methods

Results

Conclusions

Trial registration

Electronic supplementary material

Related collections

Dermal Microdialysis in Pharmacokinetics

Most cited references 15

Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council.

Poorly controlled postoperative pain: prevalence, consequences, and prevention

Local infiltration analgesia: a technique for the control of acute postoperative pain following knee and hip surgery: a case study of 325 patients.

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