Improvement in postoperative pain control plays an important role in the quality of patient recovery and satisfaction. Multilamellar vesicles formulated ropivacaine, TLC590 (Figure 1), is a clinical stage, sustainedrelease ropivacaine formulation being investigated for postsurgical analgesia via local injection. Supporting toxicology studies after subcutaneous or intramuscular administration in acute incisional wounds have been conducted in rats and miniature swine.
Materials and Methods
Groups of 12 to 14 male rats received either TLC590 at low dose, middle dose or high dose, vehicle or normal saline along the incision site (Table 1). Body weights and clinical observations were recorded daily. Six rats in each group were sacrificed on Day 3 and the remaining rats were sacrificed on Day 14 for gross observations and histopathological examination of skin (injection site).
Groups of 8 miniature swine/sex received either TLC590 at low dose, middle dose or high dose, vehicle or normal saline and groups of 4 miniature swine/sex received Naropin® along the inguinal surgical hernia site with polypropylene mesh implantation (2.5 × 5 cm) (Table 1). The animals were monitored for mortality observations, body weights, feed consumption and wound observations using modified Draize scores and wound condition scores. Four miniature swine/sex/group were sacrificed on Day 4 and the remainder were sacrificed on Day 29 for macroscopic examinations. Endpoints included necropsy and tissue collection, clinical pathology, organ weights and histopathological examination of a full tissue list including dosing site, ilioinguinal nerve and inguinal lymph nodes. Toxicokinetic samples were taken at designated time points and analyzed using LC-MS/MS.
Results and Discussion
All rats survived until scheduled termination. There were no significant differences in body weights, body weight changes, clinical observations and gross observations among all group animals. Results in rats suggested no TLC590-related and dose-related toxic effects. The histopathological examination of skins revealed no treatmentassociated effect during the wound healing process (Table 2).
No significant differences in body weights, body weight changes and clinical observations among all treatment groups in miniature swine were observed. The peak reactions, by Draize scoring, of erythema and edema on the dosing site in post-surgery monitoring appeared primarily on Day 2 or Day 3 in all groups for both genders and most of the reactions were resolved by Day 8. Similar results were observed in wound site assessment. Clinical pathology evaluations, organ weights, organ weight ratios and histopathological evaluations (Table 3) demonstrated that there were no patterns or trends in differences between treatment groups or genders indicating a correlation to TLC590 treatments either on Day 4 or Day 29.
Toxicokinetic results demonstrated that there were varying gender differences and the systemic exposure increased accordingly along with dose level increases, but less that dose-proportionally (Figure 2 and Table 4).
A NOAEL of TLC590 is above 40 mg/kg for a single local administration in miniature swine, which the estimated human equivalent dose is 2270 mg/human (60 kg). These data demonstrate the safety and local tolerance of TLC590 in clinically relevant models and support the first-inhuman trial of TLC590 by the wound infiltration route. A Phase I/II clinical trial to evaluate the safety, tolerability, pharmacokinetics and efficacy of TLC590 in patients was completed.