A sustained-release DepoFoam injection formulation of bupivacaine (EXPAREL, 15 mg/mL) is currently being investigated for postsurgical analgesia via peripheral nerve block (PNB). Single-dose toxicology studies of EXPAREL (9, 18, and 30 mg/kg), bupivacaine solution (Bsol, 9 mg/kg), and saline injected around the brachial plexus nerve bundle were performed in rabbits and dogs. The endpoints included clinical pathology, pharmacokinetics, and histopathology evaluation on Day 3 and Day 15 (2/sex/group/period). EXPAREL resulted in a nearly 4-fold lower C max versus Bsol at the same dose. EXPAREL was well tolerated at doses up to 30 mg/kg. The only EXPAREL-related effect seen was minimal to mild granulomatous inflammation of adipose tissue around nerve roots (8 of 24 rabbits and 7 of 24 dogs) in the brachial plexus sites. The results indicate that EXPAREL was well tolerated in these models and did not produce nerve damage after PNB in rabbits and dogs.

EXPAREL (bupivacaine extended-release liposome injection), DepoFoam bupivacaine, is in development for prolonged postsurgical analgesia. Repeat-dose toxicity studies were conducted in rabbits and dogs to compare the potential local and systemic toxicities of EXPAREL and bupivacaine HCl (Bsol), and the reversibility of any effects. Dogs tolerated much larger doses than rabbits. EXPAREL-related minimal-to-moderate granulomatous inflammation was noted at the injection sites. In recovery animals, the granulomatous inflammation was observed less frequently and was characterized by an increased number of multinucleated giant cells. These effects were considered a normal response to liposomes and nonadverse. Rabbits are more sensitive than dogs. In rabbits, convulsions were noted with EXPAREL and more frequently with Bsol; a NOAEL was not identified. In dogs, EXPAREL was well tolerated (NOAEL > 30 mg/kg/dose). The cumulative exposure of EXPAREL in these studies is well in excess of the proposed maximum single-dose exposure that is intended in humans.

The data reported here are the first demonstration of the safety of DB in toxicology species.

A previous study in rats showed that even though probucoi substantially lowers high density lipoprotein (HDL) levels, near-normal mass transport of HDL cholesterol esters (CE) to the liver is maintained by the induction of "selective" (direct) uptake of HDL CE. The present study describes a parallel result in cultured Hep G2 human hepatoma cells. Cells were preincubated in the presence or absence of probucoi before measuring the uptake of doubly labeled HDL, in the absence of probucoi. Preincubation with probucoi decreased the uptake of HDL, particles (iodine-125-labeled JV-methyltyramlne cellobioseapolipoprotein [ 12J I-NMTC-apo] A-I uptake) but increased the uptake of [ 3 H]cholesteryl oleyl ether in excess of I2! I-NMTC-apo A-I (i.e., selective uptake) in a dose-dependent fashion. The reversibly cell-associated pool of CE tracer, a precursor for selective uptake, enlarged on probucoi treatment, but the increase was not in proportion to the increase in selective uptake. HDL, particle uptake decreased on probucoi treatment The decrease was evident after <20 minutes of probucoi exposure and was maximal after 6 hours; in contrast, HDL, CE selective uptake increased only after > 13 hours and had not reached a plateau after 20 hours. Thus, effects on particle uptake and selective uptake were dissociated in time. 1992;12:870-878) KEY WORDS • probucoi • Hep G2 human hepatoma cells • cholesterol ester transport P robucoi has a modest plasma cholesterol-lowering effect in humans, yet the drug inhibits xanthomatosis and causes regression of existing xanthomas in patients with familial hypercholesterolemia. (Arteriosclerosis and Thrombosis1 Probucoi also inhibits the development of aortic lesions of Watanabe heritable hyperlipidemic rabbits, which are deficient in low density lipoprotein (LDL) receptor activity.2 In these cases probucoi does lower plasma LDL cholesterol levels, but the decrease is generally accompanied by a fractionally similar decrease in high density lipoprotein (HDL) cholesterol levels. -3This decrease is worrisome because HDL is believed to mediate "reverse" cholesterol transport from peripheral cells to the liver. 4 Paradoxically, there is a positive correlation between the extent of xanthoma regression caused by probucoi and the decrease in plasma HDL cholesterol levels. 1Lower HDL levels do not necessarily signify diminished reverse cholesterol transport. In a previous study 5 we found that treating rats with probucoi did not significantly decrease the mass transport of HDL cholesterol esters (CE) to the liver, in spite of a >30% decrease in plasma HDL cholesterol levels. Whereas Received May 28, 1991; revision accepted March 24, 1992. the fractional rate of HDL CE uptake by the liver increased while the fractional rate of HDL apolipoprotein (apo) A-I uptake did not change, the maintenance of near-normal HDL CE uptake was ascribed wholly to increased selective uptake and not to endocytotic uptake of HDL particles. This in vivo result is consistent with an earlier in vitro study 6 in which ex...

We explored the potential for EXPAREL to interact with lidocaine. Sixty (60) male Yucatan Swine were randomized into 20 groups (N = 3/group). EXPAREL (2 or 4 mg/kg) and/or lidocaine HCl solution 1% or 2% (with epinephrine 1 : 200,000) were injected subcutaneously along a 5 cm virtual incision line. The effects on the pharmacokinetics of bupivacaine and lidocaine were examined when 5, 10, 20, and 40 minutes had passed between administration of lidocaine and EXPAREL. Systemic exposure to lidocaine was increased (AUC0−24 hr by 48%; C max by 1,640%) when lidocaine (4 mg/kg) was followed 5 minutes later by EXPAREL (4 mg/kg) compared to lidocaine administered alone. Plasma bupivacaine was increased (AUC0−24 hr by 50–95%; C max by 67–1,000%) when lidocaine (4 mg/kg) was followed 5 or 10 minutes later by EXPAREL (4 mg/kg) compared to EXPAREL alone. While EXPAREL should not be admixed with lidocaine, this study shows that local administration of EXPAREL after at least 20 minutes following local administration of lidocaine did not increase the release of either drug.