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

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Early and satisfactory postsurgical analgesia is important because suboptimal acute-pain management can lead to increased patient morbidity, impaired physical function and quality of life, increased cost of care, and a transition from acute to chronic pain and delayed recovery [1]. Local anesthetics (LA) are commonly used during open inguinal hernioplasty, but management is difficult and often inadequate [2, 3]. Historically, opioids have been the mainstay of postsurgical pain management and, while effective for certain types of pain, their use poses significant risks [1, 4].

Infiltration of the surgical site with LAs, such as bupivacaine hydrochloride (HCl), is frequently part of a multimodal pain management regimen to limit opioid use [5]. However, surgical site infiltration produces short-lived analgesia because analgesic efficacy depends on the anesthetic remaining in the vicinity of the nerves [6, 7]. Furthermore, there are safety risks with infiltration, including local anesthetic systemic toxicity (LAST) due to accidental intravascular injection and dosing errors, which can be serious or fatal [6, 8‐12]. The dose and rate of bupivacaine HCl infiltration are the pharmacokinetic (PK) parameters most closely associated with the risk for toxicity [6, 10]; however, there is no method of monitoring administration procedures to eliminate this risk [6].

INL-001, a 5 cm × 5 cm × 0.5 cm bioresorbable implant comprised of collagen containing 100 mg of homogeneously dispersed bupivacaine HCl [13], is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 h following open inguinal hernia repair [14]. It is a single-application, ready-to-use product designed for the management of acute postsurgical pain through the immediate and extended release of bupivacaine [13]. Preclinical studies demonstrated significant reabsorption within 1 month and no microscopically observable collagen at 2 months. Additional studies have demonstrated that commonly used surgical materials are not affected by INL-001 (unpublished data, Innocoll Inc.).

Local placement of INL-001 within multiple soft tissue layers during surgery offers a novel way to deliver bupivacaine HCl directly to the source of pain, while avoiding the risk of dosing errors and inadvertent intravascular injection.

The safety and efficacy of INL-001 have been evaluated in 11 clinical trials, with 892 patients having received INL-001 implants (612 INL-001; 280 placebo implants). In two pivotal phase 3 studies, MATRIX-1 and MATRIX-2 (N = 624 patients, 411 treated with INL-001 and 208 treated with placebo), the primary efficacy endpoint of the sum of pain intensity from 0 to 24 h (SPI24) after open inguinal hernioplasty was investigated [13]. Patients in these studies received either INL-001 or placebo implants and were discharged shortly after surgery. Individually, both studies demonstrated that INL-001 300 mg significantly reduced SPI24 (MATRIX-1, p ≤ 0.0004; MATRIX-2, p < 0.0001) and led to significantly less total use of opioids in the first 24 h after surgery (MATRIX-1, p < 0.0001; MATRIX-2, p < 0.0001), compared with placebo [13]. The MATRIX-2 study demonstrated significant reductions in pain (p = 0.0270) and total opioid use (p = 0.0003) through 48 h with INL-001, and the MATRIX-1 study demonstrated a similar magnitude of effect in the reduction of pain without reaching significance (p = 0.0568). There was no statistically significant treatment effect for INL-001 compared with placebo for pain reduction or total use of opioids through 72 h (not tested in MATRIX-1; MATRIX-2, p = 0.1490); however, there was a higher proportion of patients who did not receive opioid rescue analgesia in the INL-100 versus placebo group in both studies. In MATRIX-1, through 72 h after surgery, 36% of INL-001-treated patients and 22% of placebo-treated patients did not use any opioids (MATRIX-2 values were 28% and 12%, respectively) [13]. Based on overall data, INL-001 received approval by the US Food and Drug Administration (FDA) with an indication for use in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 h following open inguinal hernia repair.

The primary objective of this study (NCT03234374) was to evaluate the PK profile of INL-001 300 mg compared with 0.25% bupivacaine HCl 175 mg infiltration. The maximum concentration was identified as a key PK parameter for comparison because it is generally thought to be the primary driver of systemic bupivacaine toxicity [10]. The secondary objective of this study was to assess the safety and tolerability of INL-001, with emphasis on wound healing and the signs and symptoms of bupivacaine toxicity.

This multicenter, randomized, single-blind, active comparator-controlled study (NCT03234374 posted on July 31, 2017, at https://​clinicaltrials.​gov/​ct2/​show/​NCT03234374?​term=​inl-001&​draw=​2&​rank=​1) enrolled men and women aged ≥ 18 years that were undergoing elective unilateral inguinal hernioplasty via open laparotomy. The repair of multiple hernias through a single incision was permitted. This trial enrolled patients across five sites in the US from June through August 2017. Patients were randomized to receive either three INL-001 (Xaracoll^®, Innocoll Pharmaceuticals Ltd., Athlone, Ireland) 100 mg bupivacaine HCl implants, for a total of 300 mg bupivacaine HCl (n = 35), or local infiltration of 0.25% bupivacaine HCl (Marcaine) 175 mg (n = 17).

The protocol and statement of informed consent were approved by an Institutional Review Board (IRB) prior to each center’s initiation (see Table S1 in Supplementary materials). All procedures were conducted in accordance with the Declaration of Helsinki, and the study was conducted in compliance with Good Clinical Practice guidelines. Informed consent was obtained from all participants. In addition, eligible individuals must have had the ability and willingness to comply with study procedures and to use only permitted medications (including opioids).

Patients were excluded from enrollment if they had a known hypersensitivity to amide local anesthetics, morphine, acetaminophen, or bovine products. Patients were also excluded if they were scheduled for bilateral inguinal hernia repair or another significant surgical procedure concomitantly. In addition, eligible patients could not have undergone major surgery within 3 months of initial treatment nor were they permitted to have another laparotomy procedure planned for within the 30-day postsurgical period. Also, patients with a known or suspected history of alcohol or drug abuse or misuse within 3 years of screening or a clinically significant unstable cardiac, neurologic, immunologic, renal, hepatic, or hematologic disease or any other significant condition were excluded.

Enrolled patients underwent elective unilateral inguinal hernioplasty via open laparotomy according to standard procedures. In the INL-001 group, three implants (each containing 100 mg of bupivacaine HCl) were cut in half; these six implants were placed in protocol-defined locations in the surgical site. After the hernia sac was reduced and the mesh was ready for insertion, three of the six implants were placed into the hernia repair site below the site of mesh placement. The mesh placement was completed per the surgeon’s typical technique. The external oblique aponeurosis was closed, and the remaining three implants were placed between the fascia/muscle closure and skin closure. The subcutaneous tissue and skin were closed per the surgeon’s preferred method. If the surgeon encountered a significant surgical or medical complication, there was the option not to administer the study drug; this patient would be considered randomized, but not enrolled or treated. The comparator group was treated with 0.25% bupivacaine HCl 175 mg infiltrated into the muscular planes of the transverse abdominis and interior oblique muscles as well as the surrounding subcutaneous tissues. This dose of bupivacaine HCl (175 mg) was chosen because it represents a common clinically used dose per the prescribing information for bupivacaine HCl injection (Marcaine) and was the dose predicted to most closely result in a maximum concentration similar to that of INL-001 300 mg.

Following surgery, patients were transferred to a postanesthesia care unit (PACU) until stable and then moved to the clinic where they were allowed to receive parenteral morphine, if needed, as a rescue medication for breakthrough pain. Once patients were able to tolerate oral medication, they were started on a standardized oral analgesic regimen of acetaminophen 650 mg three times daily (TID). They were prescribed immediate-release morphine (15 mg) to manage breakthrough pain.

Fifty-two patients were randomized to the study. Of the 35 patients in the INL-001 group, 34 (97.1%) completed the study and 1 (2.9%) was randomized but not enrolled. Of the 17 patients in the 0.25% bupivacaine HCl infiltration group, 16 (94.1%) completed the study and 1 (5.9%) was randomized but not enrolled (Fig. 1).

The 50 patients enrolled comprised the safety, PK, and per-protocol PK populations, all of whom received INL-001 or 0.25% bupivacaine HCl infiltration, had at least one postimplantation/infiltration blood sample obtained, had no major PK-related protocol deviation, and had sufficient data to calculate the C_max, AUC_0–last, and AUC_0–∞ for either INL-001 or 0.25% bupivacaine HCl infiltration. Table 1 summarizes demographic and baseline characteristics by treatment for the safety population. Demographics were comparable across the treatment groups, and most patients were male (98.0%) and white (92.0%); the mean ± standard deviation (SD) age was 44.3 ± 14.0 years. No clinically significant abnormalities were reported for the physical examinations performed at screening.

INL-001 is a drug-device combination that delivers bupivacaine HCl, utilizing a collagen-matrix drug delivery technology designed to be implanted in the surgical site at the time of elective open inguinal hernia repair. This study supports that INL-001 begins to release bupivacaine immediately upon placement in the surgical area and provides a continued release of bupivacaine over time, as evidenced by quantifiable bupivacaine concentrations at the first time point measured (0.5 h) through the last time point measured (96 h).

For the INL-001 dose of 300 mg of bupivacaine HCl, which has been shown to be effective for pain relief and well tolerated in clinical trials of open inguinal hernia repair [13], the mean maximum concentrations were comparable with a commonly used 175 mg dose of bupivacaine HCl. A prolonged rate of bupivacaine absorption and clearance was observed when delivered by INL-001 compared with 0.25% bupivacaine HCl infiltration, as demonstrated by the median time to maximum concentration being three times that of infiltrated bupivacaine HCl and the mean half-life being twice as long. At 36 h, the mean bupivacaine concentration with INL-001 was twice that of 0.25% bupivacaine HCl infiltration and five times greater at 96 h.

The peak bupivacaine plasma concentrations for both treatment groups (1230 ng/mL for the INL-001 group and 1140 ng/mL for the bupivacaine HCl infiltration group) were comparable. The highest individual bupivacaine plasma concentration observed in the INL-001 clinical development program was 38% and 69% lower than the threshold concentrations that have been associated with the signs and symptoms of bupivacaine central nervous system toxicity (> 2000 ng/mL) and cardiovascular toxicity (> 4000 ng/mL), respectively [6, 10]. There was also no clinical evidence of systemic bupivacaine toxicity in either treatment group in this study.

Overall, INL-001 was found to be well tolerated. Somnolence was the most common TEAE observed in both the INL-001 and the 0.25% bupivacaine HCl infiltration treatment groups. The most common AEs reported in both groups were expected in a post general anesthesia setting and with the use of opioids, consistent with the known profile of bupivacaine. Although there were signs and symptoms related to wound healing reported by individuals from both treatment groups, the frequency of postsurgical wound healing-related events was overall lower than that reported in the literature for inguinal hernia surgery [15]. Additionally, all but one of the wound healing-related events were mild in severity. Only one patient had wound-healing events whose symptoms lasted > 14 days, and all events related to the surgical wound were manageable and resolved.

Bupivacaine HCl and bovine type I collagen have established safety profiles and have been available and used for many years in the healthcare setting [16]. INL-001, as a drug-device combination, has a demonstrated safety profile consistent with each of these components. The collagen that makes up the collagen matrix of the implant is sourced from purified, biocompatible, bioresorbable bovine type I collagen. Bovine type I collagen is used in numerous clinical applications and shares a common amino acid structure and surface epitopes with human type I collagen, resulting in a negligible risk for an immune response. No risks or allergic reactions related to the collagen have been reported with the use of INL-001. Additionally, due to the unique bioresorbable implant formulation of INL-001, risks associated with liquid bupivacaine formulations such as accidental intravascular injection and preparation-related dosing errors are avoided.

The predominantly white and male patient population is a limitation to this study. A strength of this study is that it includes a dose of bupivacaine HCl that is commonly used in surgical infiltration as a comparator for evaluation of pharmacokinetics [13, 17‐20]. Based on findings from the pivotal phase 3 MATRIX-1 and MATRIX-2 studies [13], INL-001 received FDA approval for placement into the surgical site to produce postsurgical analgesia for up to 24 h following open inguinal hernia repair in adults. In the MATRIX studies, fewer patients needed opioids with INL-001 postoperatively through 72 h compared to placebo-treated patients [14]. The results from this study support the benefits of INL-001 by demonstrating prolonged bupivacaine exposure, which aligns with the significant reduction in both postsurgical pain and opioid consumption observed with INL-001 treatment in the MATRIX studies [13]. The AEs that did occur in the study described here were mild in severity (one moderate and no severe events in the INL-001 group), and the overall safety profile was similar to that seen in the MATRIX studies, with INL-001 being well tolerated.

This PK evaluation supports that INL-001 begins to release bupivacaine immediately upon placement in the surgical area, with a relatively rapid rise in the bupivacaine concentration, and provides an extended release of bupivacaine over time relative to 0.25% bupivacaine HCl 175 mg infiltration. Treatment with INL-001 was well tolerated, with no evidence of an adverse effect on wound healing or of bupivacaine toxicity in patients undergoing elective unilateral inguinal hernioplasty via open laparotomy.