Optimizing Lidocaine Dosing in Hepatectomy Patients: A Population Pharmacokinetic Study of Active Metabolites

Lidocaine and its active metabolites are metabolized mainly by the liver, and liver-compromised may slow the metabolism of lidocaine and its active metabolites. In addition to excessive lidocaine, accumulated active metabolites may also lead to lidocaine-related toxicity in liver-compromised patients. This study aimed to describe the population pharmacokinetics of lidocaine and its active metabolites in partial hepatectomy patients and propose a novel drug regimen involving lidocaine-weighted active metabolites.

The concentrations of lidocaine and its active metabolites from thirty-five patients underwent partial hepatectomy were analysed by non-linear mixed-effects models. The mean loading dose was 86.07 mg, and the median continuous infusion dose was 57.97 mg/h. A population pharmacokinetic model fitting the plasma concentrations of lidocaine and its active metabolites was built to explore the factors affecting the concentrations of lidocaine and its active metabolites.

A two-compartment model with first-order elimination was used to determine the concentrations of lidocaine and its active metabolites. The different dosing simulations revealed that the selected appropriate loading dose did not exceed 1.5 mg/kg, and the continuous infusion dose of lidocaine should preferably not surpass 1.5 mg/kg/h in Chinese hepatectomy patients. The simulation results of long-term infusion of lidocaine during the postoperative stage after liver resection that showed there was a significant accumulation of MEGX after more than 24 hours of lidocaine infusion, and when the infusion rate reached 1 mg/kg/h, the MEGX concentration exceeded 5 µg/mL.

This study proposes for the first time the integration of lidocaine concentration with active metabolites and simulation-based dosing recommendations. During the 24-hour medication period for Chinese hepatectomy patients, the recommended safe dosage includes a loading dose not exceeding 1.5 mg/kg and an infusion dose not exceeding 1.5 mg/kg/h. Monitoring of active metabolites, in addition to lidocaine is also necessary for continuous infusion of lidocaine.

The trial is registered at chictr.org.cn (ChiCTR2100042730).