SummaryIntroductionEvidence 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.MethodsA 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.ResultsThirty 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.DiscussionOur 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.

中文翻译：

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通过群体药代动力学分析优化 1-3 级肥胖患者静脉注射利多卡因的剂量


摘要简介缺乏支持肥胖患者术中利多卡因输注方案的证据，存在剂量不足或毒性的风险。我们旨在测量利多卡因及其活性代谢物的血浆浓度，以开发肥胖患者的药代动力学模型和优化给药方案。方法对 BMI ≥ 30 kg.m‐2 接受择期腹腔镜腹部手术的患者采用基于体重的标准化静脉注射利多卡因方案。使用瘦体重，在 10 分钟内给予 1.5 mg.kg-1 负荷剂量，并在术中输注 1.5 mg.kg-1.h-1。在输注期间和之后取样动脉血。使用液相色谱-质谱法测量利多卡因、单乙基甘氨酸酰亚胺和甘氨酸酰亚胺的总血浆浓度和未结合血浆浓度。Monolix 用于群体药代动力学分析。使用 Simulx 进行剂量模拟，以开发一种最针对 2.5 至 5 μ g.ml-1 之间的治疗血浆浓度的方案.结果30 名患者提供了 221 份血浆样本 （中位 （IQR [范围]） 年龄 51 （44-61 [32-76]） y 和 21 名女性）。中位（IQR [范围]）总体重为 107.0 （91.8-132.5 [80.0-189.0]） kg，BMI 为 37.7 （33.6-46.5 [30.2-58.4]） kg.m-2。使用利多卡因、单乙基甘氨酸酰亚胺和甘氨酸酰亚胺的总血浆和未结合血浆浓度，开发了一个四室模型。未结合的利多卡因分布容积为 2.1 l.kg-1，清除率为 1.7 l.kg-1.h-1。模拟表明，目前使用的剂量达到目标的可能性很低，为 0%。在 20 分钟内输注 2 mg.kg-1 的负荷剂量，然后根据瘦体重输注 3 mg.kg-1.h-1，将达到目标的可能性提高到 18.6%。 80 分钟后，输注量应减少至 2 mg.kg-1.h-1。讨论我们的模拟给药方案在肥胖患者中更成功地达到了治疗浓度。进一步的研究应评估这种给药方案的临床安全性和有效性。