Dosing optimisation of intravenous lidocaine in patients with class 1–3 obesity by population pharmacokinetic analysis

Abstract

Introduction

Evidence to support intra-operative lidocaine infusion regimens in patients with obesity is lacking, risking underdosing or toxicity. We aimed to measure the plasma concentrations of lidocaine and its active metabolites to develop a pharmacokinetic model and optimised dosing regimen in patients with obesity.

Methods

A standardised weight-based intravenous lidocaine regimen was administered to patients with a BMI ≥ 30 kg.m^-2 undergoing elective laparoscopic abdominal surgery. Using lean body weight, a 1.5 mg.kg^-1 loading dose over 10 min and infusion of 1.5 mg.kg^-1.h^-1 was administered intra-operatively. Arterial blood was sampled during and after the infusion. The total and unbound plasma concentrations of lidocaine, monoethylglycinexylidide and glycinexylidide were measured using liquid chromatography-mass spectrometry. Monolix was used for population pharmacokinetic analysis. Dosing simulations were performed using Simulx to develop a regimen that best targeted a therapeutic plasma concentration between 2.5 and 5 μg.ml^-1.

Results

Thirty patients provided 221 plasma samples (median (IQR [range]) age 51 (44–61 [32–76]) y and 21 female). Median (IQR [range]) total body weight was 107.0 (91.8–132.5 [80.0–189.0]) kg and BMI was 37.7 (33.6–46.5 [30.2–58.4]) kg.m^-2. Using total and unbound plasma concentrations of lidocaine, monoethylglycinexylidide and glycinexylidide, a four-compartment model was developed. Unbound lidocaine volume of distribution was 2.1 l.kg^-1 and clearance 1.7 l.kg^-1.h^-1. Simulations showed that doses used currently had a low probability of target attainment of 0%. A loading dose of 2 mg.kg^-1 over 20 min followed by an infusion of 3 mg.kg^-1.h^-1 based on lean body weight improved probability of target attainment to 18.6%. The infusion should be reduced to 2 mg.kg^-1.h^-1 after 80 min.

Discussion

Our simulated dosing regimen achieved therapeutic concentrations more successfully in patients with obesity. Further studies should evaluate the clinical safety and efficacy of this dosing regimen.