3). Table 3 Mean pharmacokinetic parameters for bupivacaine in rabbits receiving twice weekly subcutaneous bolus doses of DepoFoam bupivacaine (EXPAREL) or bupivacaine HCl solution (mean ±SD; N = 3/sex/group). In both species, the kinetic release profile was consistent with sustained release of the drug from the delivery system at the site of administration (Figures ​(Figures3,3, and ​and4).4). The attenuation of C max was on the order of two- to threefold compared to Bsol after the first dose. Inhibitors,research,lifescience,medical The accumulation was more evident at the 30mg/kg dose

in rabbits compared to dogs. Figure 3 Mean plasma concentrations of bupivacaine following subcutaneous injection of DepoFoam bupivacaine (SKY0402, aka EXPAREL) and bupivacaine

HCl solution in rabbits (values represent mean ± SD, N = 3/sex/group). SKY0402: previous designation for … Figure 4 Mean plasma concentrations of bupivacaine following subcutaneous administration of Inhibitors,research,lifescience,medical DepoFoam bupivacaine (SKY0402, Inhibitors,research,lifescience,medical aka EXPAREL) and bupivacaine HCl solution in dogs (values represent mean ± SD, N = 3/sex/group). SKY0402: previous designation … 4. Discussion When interpreting toxicology results, consideration has to be given to the particular sensitivity of the species to local reactions. The rabbit is, as a general rule, Inhibitors,research,lifescience,medical more sensitive than other species to the action of most substances [12]. The sensitivity of the rabbit is due to the thinness of the skin layer and the relative absence of sc fat [13]. It is not surprising therefore that a series of twice weekly injections of EXPAREL in which each exposure would progressively intensify the degree of sensitivity Inhibitors,research,lifescience,medical may cause local irritation from prolonged tissue exposure. After several repeat injections, the compartments are nearly Raf targets saturated and therefore may no longer protect against potentially toxic concentrations. Also, when assessing the potential existence of cumulative

systemic effects of bupivacaine, the resulting plasma kinetics no is an important safety consideration because systemic absorption of bupivacaine causing rapid high peaks are associated with a more pronounced risk of CNS and CV effects. A brief review of the literature is provided below. The toxic response of bupivacaine is characterized by a complex interaction between the CNS and CV systems. The response, at least in part, depends on how fast the drug is administered, and the resultant blood/tissue concentrations in target tissues are affected. Particularly, injection of repeated doses of local anesthetics may cause significant increases in plasma levels with each repeated dose due to slow accumulation of the drug or its metabolites or to slow metabolic degradation.