Population Pharmacokinetics and Pharmacodynamics of Immunoglobulins: A Systematic Review

Intravenous and/or subcutaneous immunoglobulins (IVIg/SCIg) are used as immunoglobulin replacement therapy (IgRT) in primary and secondary immunodeficiencies (PID/SID) and as immunomodulatory therapy in immune-mediated diseases. Despite empiric immunoglobulin G (IgG) target concentrations in PID, dosing remains variable and suboptimal, particularly in immune-mediated diseases lacking clear IgG target concentrations. Population pharmacokinetic (popPK) and pharmacodynamic (PD) modelling may clarify interindividual variability and support individualised dosing. Recent developments extend beyond PID, emphasising the importance of integrated PK-PD approaches to optimise IgG therapy. This review aimed to provide a comprehensive overview of popPK(-PD) models describing polyclonal IgG therapy, and to emphasise the added value of PK-PD in understanding drug behaviour.

A systematic literature search was conducted in Embase, MEDLINE, and Web of Science from inception to August 2025. Studies describing popPK(-PD) models for exogenous polyclonal IVIg and/or SCIg administration in humans were included.

In total, 14 studies were included. While most popPK models focus on PID (N = 10), an increasing number address immune-mediated diseases. Immunoglobulin G pharmacokinetics are typically described using two-compartment models with first-order kinetics, using body weight (BW) as a common covariate for clearance and volume of distribution. Endogenous IgG is often incorporated as a fixed PK parameter; however, this may not adequately capture interindividual variability and potential effects of Ig treatment on IgG concentrations. Two popPK-PD models link IgG concentrations to clinical outcomes in immune-mediated diseases. In contrast, such models are currently lacking for PID. Simulations showed consistent predicted IgG concentrations following SCIg in PID, while IVIg models in PID showed more variability.

PopPK models have advanced understanding of IgG PK and its variability between patients and treatment regimens. These models provide a powerful framework to support individualised dosing strategies, thereby potentially reducing reliance on empirical, trial-and-error dosing approaches. However, clear target concentrations are lacking and must be established for individual patients. Models may be further optimised by incorporating essential Neonatal Fc receptor (FcRn) mechanisms using physiology-based pharmacokinetic (PBPK) or semi-mechanistic models. In conclusion, current models are useful to predict IgG concentrations across diseases during Ig treatment; however, a clearer relationship with PD is required. Hence, these findings can guide clinical trial design for tailored dosing regimens.