A new look at an old friend: Using contemporary analysis to examine the population pharmacokinetics of intravenous immunoglobin

Background Immunoglobulin G (IgG) is a unique and valuable therapeutic blood product which has been used for >60 years for replacement in both primary and secondary antibody deficiencies. Its efficient use remains important, particularly given growing demand as treatment for autoimmune conditions. Understanding its pharmacokinetics and pharmacodynamics (PK/PD) is required for the application of precision medicine. Given the lack of an appropriate population model in the literature, the current study was designed to provide a basis for further studies by developing a population pharmacokinetic model of IgG and its subclasses in patients receiving intravenous immunoglobulin (IVIg) as antibody replacement. Methods Over six months multiple samples are planned from each patient, with trough and peak samples taken during visits to the day ward. To reduce study burden on patients, inter‐dose samples have wide sampling windows and will be collected at each patients’ local pathology centre. Clinical and laboratory characteristics will be assessed as potential covariates including size, comorbidities and inflammatory markers. Non‐linear mixed effects modelling will analyse the concentrations for all patients simultaneously to provide a population model. Simulation studies were carried out to assess the planned study design. Results Approximately two thirds of eligible patients consented to participate in the study, testament to the novel, less onerous study design. Simulations and preliminary analyses demonstrated i) endogenous production can be differentiated from administered IgG ii) covariates affecting the half‐life by as little as 30% can be detected iii) a population model can be used to predict future trough levels prior to steady state iv) appropriate size covariates (i.e. body weight vs ideal body weight) can be assessed. Conclusions The developed population PK model will establish a foundation for the study of PK/PD in more complex situations including subcutaneous immunoglobulin replacement and high dose IVIg in patients with autoimmune conditions.