Background: Perioperative IV lidocaine infusions show promise for pain reduction and enhanced postoperative recovery. However, a lack of definitive data regarding optimal dosing, safety, and efficacy has led to controversy and limited its adoption. Additionally, uncertainty surrounds the role of lidocaine’s major metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in its overall effects. This study used non-linear mixed-effects modelling to characterise the pharmacokinetics (PK) of lidocaine and its metabolites in adult surgical patients.
Methods: A single-centre, prospective PK study was conducted. Thirty-four donor nephrectomy and sixty-four cholecystectomy patients received intraoperative IV lidocaine infusions. Perioperative plasma samples were collected and analysed using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MSMS). Lidocaine and metabolite concentration-time data were analysed sequentially and then simultaneously using NONMEM. Covariate effects and alternative dosing regimens were investigated.
Results: A total of 1,520 concentration-time points were analysed, including values below the lower limit of quantitation but above the limit of detection. Lidocaine PK was best described by a 3-compartment model, while MEGX and GX followed 2-compartment models. The central compartments were linked sequentially, with a transit compartment between lidocaine and MEGX. All parameters were scaled allometrically with total body mass and fat-free mass (FFM). Lidocaine had a typical clearance of 45.9 L/h, which decreased by 60% postoperatively, and a central volume of 25.2 L. Peripheral compartments 1 and 2 exhibited intercompartmental clearances of 142 L/h and 5.81 L/h, with volumes of 44.4 L and 29.3 L, respectively. Peripheral compartment 1’s volume expanded with intraoperative fluid administration. Simulations suggested that an FFM-based lidocaine dosing regimen (bolus: 2.5 mg/kg over 30 minutes, single infusion: 2 mg/kg over 1 hour, maintenance infusion: 1.5 mg/kg/h) rapidly achieved and maintained a lidocaine target plasma concentration of 1.5 mg/L.
Conclusions: The joint parent-metabolites popPK model effectively characterises the disposition of lidocaine and its metabolites, incorporating allometric scaling and key covariates. This model provides a foundation for optimising lidocaine dosing and guiding future research to establish target plasma concentrations for safe and effective use in the general surgical population. Additional studies are warranted to refine and evaluate the model’s applicability in other surgical cohorts.