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 (AUC(0-24 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 (AUC(0-24 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.

Figures

Figure 1

Diagram showing the dose equally distributed as 6 serial bolus injections along a 5 cm virtual incision line.

Figure 2

Diagram showing the approximate area where subcutaneous injections were administered on each animal (i.e., scapular region).

Figure 3

Mean systemic exposure parameters (±SD) for plasma lidocaine (a) and bupivacaine (b) after high (4 mg/kg) subcutaneous dose of lidocaine/epinephrine and EXPAREL (N = 3/group unless noted). Series 1: AUC0−24 hr (ng/mL·hr). Series 2: Cmax⁡ (ng/mL). Notes: SD was not calculated for mean plasma bupivacaine concentrations at 5 minutes (N = 2) because one animal received 55% of the intended dose of EXPAREL; therefore, data from this animal were not used in calculation of means; individual values for AUC0−24 hr = 2,980 and 5,770 ng/mL·hr and for Cmax⁡ = 3,690 and 7,770 ng/mL.

Figure 4

Mean systemic exposure parameters (±SD) for plasma lidocaine after high (4 mg/kg) subcutaneous dose of lidocaine/epinephrine and EXPAREL (N = 3/group).

Figure 5

Systemic exposure parameters (±SD) for plasma bupivacaine after high (4 mg/kg) subcutaneous dose of lidocaine/epinephrine and EXPAREL (N = 3/group unless noted). Notes: SD was not calculated for bupivacaine at 5 minutes (N = 2, AUC = 2,980 and 5,770 ng/mL·h; Cmax⁡ = 3,690 and 7,770 ng/mL).