Background and Objective

Intravenous immunoglobulin (IVIg) at a standard dosage is the treatment of choice for Guillain–Barré syndrome. The pharmacokinetics, however, is highly variable between patients, and a rapid clearance of IVIg is associated with poor recovery. We aimed to develop a model to predict the pharmacokinetics of a standard 5-day IVIg course (0.4 g/kg/day) in patients with Guillain–Barré syndrome.

Methods

Non-linear mixed-effects modelling software (NONMEM^®) was used to construct a pharmacokinetic model based on a model-building cohort of 177 patients with Guillain–Barré syndrome, with a total of 589 sequential serum samples tested for total immunoglobulin G (IgG) levels, and evaluated on an independent validation cohort that consisted of 177 patients with Guillain–Barré syndrome with 689 sequential serum samples.

Results

The final two-compartment model accurately described the daily increment in serum IgG levels during a standard IVIg course; the initial rapid fall and then a gradual decline to steady-state levels thereafter. The covariates that increased IgG clearance were a more severe disease (as indicated by the Guillain–Barré syndrome disability score) and concomitant methylprednisolone treatment. When the current dosing regimen was simulated, the percentage of patients who reached a target ∆IgG > 7.3 g/L at 2 weeks decreased from 74% in mildly affected patients to only 33% in the most severely affected and mechanically ventilated patients (Guillain–Barré syndrome disability score of 5).

Conclusions

This is the first population-pharmacokinetic model for standard IVIg treatment in Guillain–Barré syndrome. The model provides a new tool to predict the pharmacokinetics of alternative regimens of IVIg in Guillain–Barré syndrome to design future trials and personalise treatment.

中文翻译：

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格林-巴利综合征患者静脉注射免疫球蛋白治疗的群体药代动力学模型

背景与目的

标准剂量的静脉注射免疫球蛋白 (IVIg) 是格林-巴利综合征的首选治疗方法。然而，患者之间的药代动力学差异很大，IVIg 的快速清除与恢复不良有关。我们旨在开发一个模型来预测格林-巴利综合征患者标准 5 天 IVIg 疗程（0.4 g/kg/天）的药代动力学。

方法

非线性混合效应建模软件 (NONMEM® ⁾用于构建药代动力学模型，该模型基于 177 名格林-巴利综合征患者的模型构建队列，共有 589 个连续血清样本检测总免疫球蛋白 G (IgG ) 水平，并在一个独立的验证队列中进行评估，该队列由 177 名格林-巴利综合征患者和 689 个连续血清样本组成。

结果

最终的两室模型准确地描述了标准 IVIg 过程中血清 IgG 水平的每日增量；最初的快速下降，然后逐渐下降到稳态水平。增加 IgG 清除率的协变量是更严重的疾病（如格林-巴利综合征残疾评分所示）和伴随的甲基强的松龙治疗。当模拟当前的给药方案时，在 2 周内达到目标 ΔIgG > 7.3 g/L 的患者百分比从轻度受影响患者的 74% 降至最严重和机械通气患者的仅 33%（Guillain- Barré 综合征残疾评分为 5)。

结论

这是格林-巴利综合征标准 IVIg 治疗的第一个群体药代动力学模型。该模型提供了一种新工具来预测格林-巴利综合征中 IVIg 替代方案的药代动力学，以设计未来的试验和个性化治疗。