CPL-01, A Novel Extended-Release Ropivacaine, Demonstrates Consistent and Predictable Systemic Exposure Compared to Liposomal Bupivacaine in Multiple Surgical Models

Abstract

Although several bupivacaine-based long-acting local analgesics have been approved over the past decade or so, post-operative analgesia with minimal opioid use remains elusive. One reason for this may be because the pharmacokinetics (PK) from these formulations are inconsistent across multiple surgical models, leading to reluctance to use them in any surgical model where the PK curve has not already been demonstrated for fear of Local Anesthetic Systemic Toxicity (LAST) and concerns regarding inconsistent efficacy. Ropivacaine, widely considered to be safer than bupivacaine, has been developed as a novel extendedrelease formulation (CPL-01). As there is publicly available data demonstrating the PK of liposomal bupivacaine (LB) in several of the same surgical models as CPL-01, we compared the PK of ropivacaine from CPL-01 to that of bupivacaine from LB to better understand the consistency of their systemic exposure.Approach: Data on LB's PK was used to construct a dose-normalized curve across three surgical models after a 200 mg dose. These were then graphed alongside data from CPL-01 trials in abdominoplasty, herniorrhaphy, and bunionectomy, each of which had a 200 mg dose. The curves were then compared, focusing on the consistency of the shape of the curve, the mean Cmax, and the median Tmax. Results:The shape of the systemic local anesthetic curve was consistent after administration of CPL-01 across multiple surgical models but was not consistent after administration of LB (see Figure 1). The dose-normalized Cmax values were at least 4-fold lower than the accepted threshold for LAST concentration of 2,000 ng/mL (bupivacaine) or 2,200 ng/mL (ropivacaine) for all models, with little variance for either product, 268-352 ng/mL in LB and 284-455 ng/mL in CPL-01. However, when comparing median Tmax values across all three surgical models, CPL-01 showed a consistent Tmax of 8-12 h, while the Tmax for LB varied from 2-36 h.Conclusions: Consistent median Tmax values across surgical models with CPL-01 indicates a more predictable release of ropivacaine over time across multiple surgical models that is not present with LB. Mean peak plasma concentration levels for both CPL-01 and LB were well below the known toxicity levels. When approved, the predictability and consistency of the PK parameters of systemic ropivacaine from CPL-01 may provide physicians with more assurance in using extended-release anesthetics, with greater confidence of more consistent efficacy and less fear of inadvertently contributing to LAST.