Dosing optimisation of intravenous lidocaine in patients with class 1–3 obesity by population pharmacokinetic analysis
Angela R. Tognolini, Xin Liu, Saurabh Pandey, Jason A. Roberts, Steven C. Wallis, Dwane Jackson, Victoria A. EleySummary
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.