Population Pharmacokinetic Modelling of Intravenous Immunoglobulin Treatment in Patients with Guillain-Barré Syndrome

Abstract

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.

Fig. 1

Schematic of the final model. Intravenous immunoglobulin (IVIg) enters the central (vascular) compartment (V1, central volume of distribution) directly. In this compartment, there is already an immunoglobulin G (IgG) concentration at baseline (CBAS) owing to the endogenous production. There is an exchange gradient (Q, intercompartmental clearance) from V1 to the peripheral compartment (V2, peripheral volume of distribution). Clearance (CL) of IgG takes place from the central compartment. The influence of covariates are represented in grey, with a downward-pointing or upward-pointing arrow denoting a decrease or an increase of the respective parameter. CIDP chronic inflammatory demyelinating polyneuropathy, GBS Guillain–Barré syndrome

Fig. 2

Goodness-of-fit plots for the final model. A–D Model-building cohort. A Observed concentration plotted against predicted concentration. B Observed concentration plotted against individual-predicted concentration. C Absolute individual weighted residuals (IWRES) against time. D Conditional weighted residuals against time. E–H similar to A–D but for a model validation cohort. The red line represents the smooth fit.

Fig. 3

Visual predictive checks using the final model parameter estimates for the A model-building cohort and B validation cohort (n = 1000 simulations). In B, 12 observations after 3000 h were omitted. The bold red line in the middle denotes the 50th percentile of the observations and the lower and upper lines represent the lower 5th percentile and upper 95th percentile of the observed data. The bordering shaded areas represent the 95% confidence interval of the respective percentiles of the predicted data. IgG immunoglobulin G

Fig. 4

Simulating dosing regimens. A Simulation of 1000 “typical” patients with Guillain–Barré syndrome from our cohort (all variables set on the group median) receiving the standard dose of 0.4 g/kg/day for 5 days. Data represent the median (predicted) immunoglobulin G (IgG) values over time with the shaded area denoting the 90% confidence interval. The other sub-charts show simulations with alternative conditions as follows: B the impact of disease severity (Guillain–Barré syndrome disability score [GBS-DS]); C additional treatment with intravenous methylprednisolone (MP) [500 mg for 5 days]; and D 3 versus 6-day regimen of 0.4 g/kg/day, and 2.0 g/kg in 2 days. The horizontal dashed line B–D represents an increase of 7.3 g/L of IgG compared with baseline (∆IgG); the vertical dashed line denotes the 2-week timepoint after the start of treatment.