P-124 - RFUS-301: Superior Safety and Extended Local Anesthetic Efficacy in Animal Studies

Abstract Title: RFUS-301: Superior Safety and Extended Local Anesthetic Efficacy in Animal Studies


Background: Postoperative pain management is a crucial aspect of perioperative care to facilitate recovery and improve patient outcomes. The most intensive pain occurs within the first 72 hours after surgery. The traditional treatment for post-operative pain (POP) often involves the continuous administration of analgesics through different routes, such as repeated injection of opioids or anesthetic, local anesthetic pump, or patient-controlled analgesia (PCA). Many of these methods are inconvenient and include the use of opioid drug, which increases the risk of opioid-related adverse events and addiction. Therefore, safe and efficacious post-surgical pain relief in the first 72 hours remains a significant unmet medical need.

Purpose/Objectives: We developed RFUS-301, a long-acting injectable formulation of levobupivacaine, using ANTER (A Novel Transitional Extended-Release) Gel technology to reduce postsurgical pain for 72 hours or longer. To evaluate its safety and efficacy in vivo, we conducted a series of animal studies. These studies included pharmacokinetic assessments, efficacy tests to measure its pain-relieving capabilities, and toxicity evaluations to ensure its safety for human use.


Methods: The safety and local anesthesia efficacy of the optimized RFUS-301 formulation was assessed in animal studies. The local anesthesia efficacy of RFUS-301 was evaluated using pig skin incision and rat sciatic nerve block models. In the pig skin incision model study, the Von-Frey filament test was employed to measure the anesthesia efficacy. In addition, the pig behavior and the recovery of skin incision were also monitored. In the rat sciatic nerve block model, the hotplate test was used to assess efficacy by measuring the latency of hind paw licking. The pharmacokinetic studies of RFUS-301 and levobupivacaine injection were conducted in Beagle dogs and pigs to demonstrate in-vivo extended release of levobupivacaine in RFUS-301. The in vivo toxicity of RFUS-301 were tested in both Beagle dog and Sprague Dawley rat in GLP setting.


Results: The in-vivo extended release of RFUS-301 was demonstrated in pharmacokinetic studies in both pigs and Beagle dogs. The Tmax of RFUS-301 was about 22-26 hours, significantly longer than that of levobupivacaine HCl injection. The half-life of levobupivacaine in the RFUS-301 administration group was about 22-24 hours. Consequently, the efficacy of RFUS-301 in pig skin incision models extended up to 120 hours at a dosage of 300 mg per pig. In the sciatic nerve block model, RFUS-301's efficacy exceeded 20 hours, while levobupivacaine injection lasted only 2-3 hours. Additionally, behavioral studies indicated that pigs receiving meddle to high doses of RFUS-301 experienced less distress compared to the placebo and levobupivacaine injection groups. Microscopic inspections and histopathological examinations in a mini pig skin wound healing study showed that RFUS-301 did not adversely affect skin incision recovery. In fact, both 150 and 300 mg per pig dosing groups had a positive impact on wound healing compared to the blank control and placebo groups.

The GLP toxicity study demonstrated excellent safety of RFUS-301 in animals. The MTD of RFUS-301 was greater than 450 mg/kg in rats and greater than 240 mg/kg in dogs via subcutaneous administration. The NOAEL of RFUS-301 was 450 mg/kg in rats and 90 mg/kg in dogs via subcutaneous injection.

Conclusions/Implications for future research and/or clinical care: Preclinical pharmacokinetic, pharmacodynamic, and toxicity studies of RFUS-301 in various animal species demonstrated that RFUS-301 significantly extends levobupivacaine release, resulting in prolonged anesthesia efficacy in rat sciatic nerve block and pig skin incision models. Pigs receiving high doses of RFUS-301 showed the least distress during the study. Administration of RFUS-301 at the minipig skin incision site did not impair skin recovery; in fact, doses of 150 and 300 mg/kg positively affected wound healing. GLP toxicity studies in both rats and dogs demonstrated excellent tolerance and safety profiles for RFUS-301. These findings suggest that RFUS-301 has the potential to provide superior safety and analgesic efficacy for postoperative pain relief.


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