Background and Objective <p>There is a significant medical need for improved long-acting local anesthetics to decrease postsurgical pain and reduce postoperative opioid use. While ropivacaine is considered a safer local anesthetic than bupivacaine, no long-acting ropivacaine formulation is currently marketed. Available formulations of bupivacaine show inconsistent pharmacokinetics (PK) among different surgical models, and inconsistency in PK may lead to a reluctance to use the medication owing to fear of local anesthetic systemic toxicity (LAST) or unreliable efficacy. CPL-01 is a novel extended-release formulation of ropivacaine. This analysis used existing published literature to compare the PK of CPL-01 and liposomal bupivacaine (LB) across five surgical models.</p> Methods <p>Published results of LB PK were used to construct dose-normalized curves in total knee arthroscopy, hemorrhoidectomy, and bunionectomy after a 200 mg dose, which were compared with a 200 mg dose of CPL-01 in abdominoplasty, herniorrhaphy, and bunionectomy.</p> Results <p>The shape of the CPL-01 systemic concentration curves was consistent across multiple surgical models; however, in LB it was not. The median time to peak concentration (<i>T</i>_max) of CPL-01 was 8–12 h and the median <i>T</i>_max of LB varied from &lt; 1 to 36 h. CPL-01 showed tighter ranges in average peak concentration (<i>C</i>_max) compared with average concentration (<i>C</i>_avg) ratios (less “swing”) throughout 72&#xa0;h, suggesting a more predictable and consistent release over time compared with the biphasic release in LB, with two distinct <i>T</i>_max peaks.</p> Conclusions <p>CPL-01 demonstrates a more predictable and consistent release of ropivacaine over time, in contrast to LB’s erratic and biphasic release of bupivacaine. If approved, the predictability of CPL-01 PK may give physicians greater confidence in more consistent efficacy and less fear of inadvertent LAST.</p>