The pharmacokinetics and safety of an intraoperative bupivacaine-collagen implant (XaraColl^®) for postoperative analgesia in women following total abdominal hysterectomy

Susan L Cusack,¹ Philip Reginald,² Lisa Hemsen,³ Emmanuel Umerah<sup>2

1</sup>Cusack Pharmaceutical Consulting, Burlington, NJ, USA; ²Departments of Gynaecology and Anaesthetics, Wexham Park Hospital, Slough, SL2 4HL, UK; ³Innocoll Technologies, Athlone, Ireland

Background: XaraColl^®, a collagen-based intraoperative implant that delivers bupivacaine to the site of surgical trauma, is under development for postoperative analgesia. We examined the pharmacokinetics, safety and efficacy of XaraColl following implantation in women undergoing total abdominal hysterectomy.
Methods: Three XaraColl implants, each containing 50 mg bupivacaine hydrochloride, were implanted in 12 women undergoing total abdominal hysterectomy for a benign condition. Serum samples were obtained through 96 hours for pharmacokinetic analysis. Patients received acetaminophen 1000 mg every 6 hours, diclofenac 50 mg every 8 hours, and were given access to intravenous morphine for breakthrough pain via patient-controlled analgesia during the first 24 hours. Pain intensity was assessed at regular intervals using a 100 mm visual analog scale. Safety was assessed through 30 days.
Results: The pharmacokinetic profile displayed a double peak in bupivacaine concentration with the second peak occurring up to 24 hours after the first and at a generally higher concentration. The time to maximum concentration (t_max) varied from 0.5 to 24 hours (median 12 hours) according to which peak predominated. The mean maximum concentration (C_max) was 0.22 µg/mL and the maximum individual C_max was 0.44 µg/mL, which are well below the established systemic toxicity threshold. Morphine use was generally low (mean 16.8 mg; median 6.5 mg) and compared favorably with institutional experience. At 6 hours post-surgery, 11 patients recorded pain scores ≤ 20 mm, 6 recorded ≤ 10 mm, and 2 reported no pain. Scores continued to decline throughout the study. The product was considered safe and well tolerated.
Conclusion: XaraColl exhibits a biphasic and sustained release profile that may provide a significant advance over standard wound infiltration. Considering the encouraging results from this study alongside those from other randomized controlled efficacy trials, XaraColl should be further evaluated as a postoperative analgesic in large, double-blind efficacy trials

Keywords: pain, opioid use, analgesia, anesthetic