Population Pharmacokinetics of IV Lidocaine and its Metabolites in Adult Surgical Patients

BACKGROUND: Perioperative lidocaine infusions show potential as a systemic analgesic and to enhance postoperative recovery. This study characterised the pharmacokinetics (PK) of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), in adult surgical patients using non-linear mixed-effects modelling.

METHODS: Thirty-four donor nephrectomy and 64 cholecystectomy patients received intraoperative IV lidocaine. Plasma samples were collected perioperatively and analysed in NONMEM. Covariate effects and alternative dosing regimens were investigated.

RESULTS: 1,520 concentration-timepoints were analysed. Lidocaine PK was best fitted with a 3-compartment model, while MEGX and GX used a 2-compartment model. All parameters were scaled allometrically with total body mass and fat-free mass (FFM). Lidocaine had a typical clearance of 45.9 L/h, decreasing 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 an FFM-based dosing regimen (bolus: 2.5 mg/kg over 30 min, single infusion: 2 mg/kg over 1 h, maintenance infusion: 1.5 mg/kg/h) quickly achieved and maintained a lidocaine target plasma concentration of 1.5 mg/L.

CONCLUSIONS: The joint parent-metabolites model adequately describes the disposition of lidocaine and its metabolites, incorporating allometric scaling and key covariates. It provides a foundation for optimising lidocaine dosing and guiding investigations to establish target plasma concentrations for safe and effective use in the general surgical population. Further research is warranted to refine and evaluate the model's utility in other surgical populations.