(M1330-02-07) Ropivacaine Toxicokinetics following Bony and Soft Tissue Administration in Rats and Pigs of a Novel Long-Acting Ropivacaine (CPL-01)

Purpose: Several long-acting bupivacaine local anesthetics have been approved recently to help fight the opioid crisis. Ropivacaine is widely considered to be a safer product, yet no long-acting ropivacaines are currently available. CPL-01 is an extended-release formulation of ropivacaine being developed for the management of acute postoperative pain and to decrease the need for opioids. This study assessed the toxicokinetics (TK) of ropivacaine following a single administration of Naropin or 3 escalating doses of CPL-01 directly to the surgical wound in rats and minipigs.

Methods: A bony tissue injury was created in four groups of Sprague-Dawley rats via a 5 mm hole drilled into the medial condyle of the right femur. The rats were then dosed via peri-defect administration from a surgically implanted catheter with either 27.4 mg/kg Naropin or 25, 50, or 75 mg/kg CPL-01. Similarly, four groups of miniature Yucatan swine had a soft tissue injury created via an ~10 cm abdominal incision and were dosed with either a single administration of Naropin at 8.8 mg/kg or CPL-01 at 10, 20 or 40 mg/kg via peri-incisional infiltration and instillation Blood samples were collected at predetermined times and plasma was assayed for ropivacaine by validated HPLC-MS/MS assays with calibration ranges of 1.00 to 1,000 ng/mL for both species. The TK parameters were determined by model independent methods.

Results: Ropivacaine exhibited markedly delayed absorption following CPL-01 compared to Naropin in both species. In rats, the mean T_max values ranged from 4 to 12 hours following CPL-01 compared to 1 h following Naropin. In minipigs, the mean T_max ranged from 0.25 to 12 hours following CPL-01 compared to 0.25 hour following Naropin. In rats, ropivacaine dose normalized C_max values following CPL-01 were 10.4, 9.84 and 6.87 kg·ng/mL/mg in males and 21.2, 12.2 and 6.75 kg·ng/mL/mg in females for 25, 50 and 70 mg/kg, respectively. Corresponding dose normalized AUC_(0-inf) values were 260, 290 and 267 h·kg·ng/mL/mg in males and 221, 211 and 218 h·kg·ng/mL/mg in females. Ropivacaine dose normalized C_max values following Naropin were 41.7 and 61.2 kg·ng/mL/mg for males and females, respectively, and the corresponding dose normalized AUC_(0-inf) values were 253 and 246 h·kg·ng/mL/mg. In minipigs, the mean ropivacaine dose normalized C_max values following CPL-01 were 39.2, 30.1 and 26.7 kg·ng/mL/mg in males and 53.6, 47.5 and 27.1 kg·ng/mL/mg in females for 10, 20 or 40 mg/kg, respectively. Corresponding mean ropivacaine dose normalized AUC_(0-72) values were 1,000, 689 and 905 h·kg·ng/mL/mg in males, and 1,170, 1,240 and 1,230 h·kg·ng/mL/mg in females. The mean ropivacaine dose normalized C_max values following Naropin were 341 and 344 kg·ng/mL/mg for males and females, respectively, and corresponding mean dose normalized AUC_(0-72) values were 1,020 and 1,750 h·kg·ng/mL/mg. Ropivacaine exhibited markedly prolonged elimination following CPL-01 compared to Naropin. Ropivacaine T_1/2 values following CPL-01 ranged from 18.2 to 20.2 hours in male rats, and from 29.5 to 35.1 hours in female rats. Mean T_1/2 values in minipigs ranged from 26.5 to 31.7 hours in male minipigs and from 18.6 to 31.2 hours in female minipigs. Ropivacaine T_1/2 values following Naropin were 4.02 and 3.32 hours for male and female rats and the mean T_1/2 values were 5.93 and 6.75 hours for male and female minipigs.

Conclusion: After both bony and soft tissue administration, ropivacaine exhibited markedly delayed absorption and prolonged elimination following CPL-01 compared to Naropin in both species. Ropivacaine dose normalized C_max values demonstrated a consistent and predictable pattern, showing generally lower results following CPL-01 compared to Naropin in both species, while dose normalized AUC values were generally similar. Importantly, ropivacaine C_max values in both species did not consistently increase with increasing CPL-01 dose, while AUC_(0-inf) values increased in an approximately dose proportional manner. Overall there were no consistent differences in systemic exposure between male and female rats or minipigs. These findings support further clinical study of CPL-01 as a long-acting ropivacaine-based local anesthetic and may point the way to another non-opioid option for multi-day post-operative pain control.