Swollen or thickened injection sites were noted in a low number of terminal and recovery animals. Often, there was no microscopic correlate to the red discoloration at the injection sites. In rare occasions, the red discoloration corresponded with HEM, edema, and/or sc subacute inflammation. This macroscopic finding was considered to be a result of physical trauma from the Inhibitors,research,lifescience,medical injection

procedure and not associated with treatment. On both Day 26 and Day 54, minimal-to-moderate Gi was observed in the sc tissue of male and female dogs. Similar microscopic findings were not observed in Bsol or saline control group (Figure 2). Figure 2 Injection site findings in dogs on day 54. (a): Saline control. H&E 2x, (b): BTK inhibitor Bupivacaine HCl solution, 9mg/kg. H&E 2x, (c): DepoFoam Bupivacaine 30mg/kg H&E 4x. Annotations are as follows: black arrows: vacuolated … Inhibitors,research,lifescience,medical On Day 26, Gi was characterized by numerous VMs and fewer lymphocytes, plasma cells, and/or GCs formed by fused Macs with abundant cytoplasm and nuclei scattered irregularly throughout the cytoplasm. The Gi was commonly associated with edema and/or mineralization. The mineral deposits were commonly surrounded by GCs. On Day 54, Gi was observed less frequently and was characterized by an increased number of GCs sometimes associated with mineralization,

Inhibitors,research,lifescience,medical but not edema. In one male receiving EXPAREL 9mg/kg, minimal edema not associated with inflammation was noted. In the EXPAREL groups, minimal-to-mild signs of hemorrhage, acute inflammation, erosion, epidermal exudates, and/or subacute inflammation were observed sporadically at the Inhibitors,research,lifescience,medical injection site of some terminal and recovery animals. The subacute inflammation was primarily associated with hair follicles and rarely surrounded intralesional mites consistent with Demodex canis. Inhibitors,research,lifescience,medical These findings were considered procedural. 3.3. Pharmacokinetic

Results The pharmacokinetic results are shown in Tables ​Tables22–4. Species difference was observed with lower C max (↓ 4 fold) and AUC (↓ 5 fold) for all dose levels for EXPAREL (rabbit versus dog). The same observation was made for Bsol with lower C max (↓ 4-9 fold) and AUC (↓ 4 fold). Table 2 Accumulation ratios for EXPAREL and bupivacaine HCl solution (Day 25 versus Day 1) (mean ± SD; N = 3/sex/group). Table 4 Mean pharmacokinetic parameters for bupivacaine in dogs receiving Endonuclease twice-weekly subcutaneous bolus doses of DepoFoam bupivacaine (EXPAREL) or bupivacaine HCl solution (mean ±SD; N = 3/sex/group). Systemic exposure in female rabbits on Day 25 tended to be larger than that in males (data not shown). In dogs, there was not marked or consistent gender difference with regard to the PK parameters for bupivacaine. The PK results indicate that rabbits and dogs were exposed to bupivacaine in a dose-related (although not strictly dose-proportional) manner after twice weekly repeated dosing of EXPAREL, at doses ranging from 9 to 30mg/kg.