Towards personalized immunoglobulin treatment in patients with GBS and CIDP:Pharmacokinetic modeling & biomarker studies

The overall aim of this thesis is to move towards model-informed (precision) dosing of IVIg treatment for patients with GBS and CIDP by integrating PK(PD) modeling, biomarker research, and genetic analyses. The specific objectives are: - To develop and validate the first population PK model for IVIg in patients with GBS. - To determine the relationship between IVIg PK and clinical response (PD) in patients with GBS. - To develop and validate a PK model for IVIg in patients with CIDP and determine the relationship with the clinical response (PD). - To identify novel genetic and fluid biomarkers to explain variability in IVIg PK and treatment response. - To develop a method to distinguish between endogenous and therapeutic IgG to better understand the PK of IVIg. Part I provides a systematic review of population pharmacokinetic (PK) and pharmacodynamic (PD) models in patients treated with IVIg and/or SCIg. Part II focuses on the PK and PD of IVIg in patients with GBS and CIDP. Chapter 3 describes the development of the first population PK model for standard IVIg treatment in patients with GBS and identifies covariates that explain the large variability observed between patients. The performance of this model is evaluated in a large independent cohort. In Chapter 4, the model developed in Chapter 3 is applied to explore the dose– response relationship in patients enrolled in the SID-GBS trial. Chapter 5 investigates the PK–PD relationship of IVIg maintenance treatment in patients with CIDP. Data from a large clinical trial are used to examine the association between PK and clinical outcomes in patients with CIDP. Part III explores novel biomarkers to better understand variability in treatment response and disease susceptibility. Chapter 6 introduces a novel approach to distinguish endogenous IgG, including pathogenic anti-glycolipid antibodies, from therapeutic IgG based on genetic determinants in IgG1. Chapter 7 examines whether genetic variation in the FCGR2/3 locus is associated with susceptibility, muscle weakness, clinical outcomes, and IVIg kinetics in patients with GBS. Chapter 8 describes the dynamics of NfL and evaluates its independent prognostic value during the acute phase of GBS relative to established clinical prognostic factors. Finally, Part IV discusses and summarizes the key findings presented in this thesis and outlines directions for future research.