Pharmacokinetic Compatibility Study of Lidocaine with EXPAREL in Yucatan Miniature Pigs

Abstract

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.

Multivesicular liposomal bupivacaine at the sciatic nerve

“…That tissue injury is a crucial consideration for PDLA systems is seen in the example of a sustained-release bupivacaine-dexamethasone formulation where inflammation and nerve and muscle injury in preclinical animal studies and clinical human trials led to withdrawal of its Investigational New Drug application (IND#53,441)[34]. Despite evidence suggesting that tissue injury is an important issue for all PDLA formulations containing amino-amide (and presumably amino-ester) local anesthetics, it is often not documented[1–3, 8–10, 50] (or even reported to be absent)[5]. When recognized, tissue injury is generally observed as mild granulomatous inflammation[7, 11, 13, 14, 19].…”

Serum Bupivacaine Concentration After Periarticular Injection With a Mixture of Liposomal Bupivacaine and Bupivacaine HCl During Total Knee Arthroplasty

“…7,8 Therefore, liposomal bupivacaine has been used to provide analgesia in total knee replacement surgeries by direct injection around the knee joint. 4,5,[9][10][11][12][13][14][15] However, because of its slow onset when used alone, many surgeons mix liposomal bupivacaine with bupivacaine HCl to achieve quicker onset of sodium-channel blockade. This use has gained popularity and is currently practiced at our institution, where it is injected as a mixture of liposomal bupivacaine, 0.25% bupivacaine HCl, epinephrine, and normal saline.…”

“…The FDA prescription label warns that mixing Exparel in a solution where bupivacaine HCl exceeds 50% of the liposomal bupivacaine dose may result in an alteration of the pharmacokinetic properties of the drug, potentially causing a large release of bupivacaine from liposomes. 16 In addition, the FDA label warns against mixing Exparel with any other local anesthetic 12 and recommends no additional bupivacaine HCl be given within 96 hours of administering Exparel. 16 Currently, there are no published studies demonstrating serum bupivacaine concentration over time after periarticular injection of a mixture of liposomal bupivacaine with bupivacaine HCl.…”

Local Toxicity from Local Anesthetic Polymeric Microparticles

“…32,[38][39][40] Reporting of local tissue injury from local anesthetic controlled release formulations has been variable, in both animal and human studies. Most do not describe myotoxicity [2][3][4][5][7][8][9][11][12][13][14][15]18,[22][23][24] (including the liposomal formulation undergoing human trials 16,17 ), while some others document mild muscle injury comparable to single injections of unencapsulated drug. 10,25,26 In our own work, we have found muscle injury to be a ubiquitous finding in a wide range of extended-release bupivacaine formulations independent of the delivery vehicle 6,19,21,41 or co-encapsulated agent, 32,37,42,43 and it is sometimes severe.…”

“…A very broad range of controlled release formulations have been developed to provide prolonged duration local anesthesia, including polymeric microspheres, [1][2][3][4][5][6][7] surgically implantable pellets, 8 microcrystals, 9 liposomes, [10][11][12][13][14][15] (including a formulation undergoing human clinical trials 16,17 ) lipospheres, 18 cross-linkable hyaluronic acid matrices, 19 lipidprotein-sugar particles, 20,21 cyclodextrin complexes, 22,23 liposomes loaded with cyclodextrin complexes 24 and implantable membrane matrices. 25,26 Such systems have extended the duration of nerve block to varying degrees ranging from hours to weeks, but have not been widely adopted clinically.…”