Integrated population pharmacokinetics of immunoglobulin G following intravenous or subcutaneous administration of various immunoglobulin products in patients with primary immunodeficiencies

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Plasma-derived immunoglobulin G (IgG) replacement therapy represents the current standard of care for patients with primary or secondary antibody deficiencies, and includes intravenous (IVIG), subcutaneous (SCIG) and facilitated subcutaneous (fSCIG) immunoglobulin products. A holistic understanding of the pharmacokinetics (PK) of IgG for these therapies is key to optimizing their clinical use. We developed an integrated population PK model using non-linear mixed-effects modeling based on data from eight clinical trials (each ≥ 1 year duration; n = 384 patients), which simultaneously characterized IgG PK profiles of IVIG, SCIG or fSCIG in patients with primary immunodeficiencies and identified covariate effects. The final model was a two-compartment turnover model incorporating: the endogenous production of IgG with linear subcutaneous absorption and a product effect on bioavailability; additive and proportional error; between-patient variability on clearance and central volume of distribution; and allometric scaling with lean body mass on clearance, intercompartmental clearance and central and peripheral volumes of distribution. Overall, the model adequately described IgG PK profiles, with residual standard error values < 28 % for all PK parameters. Goodness-of-fit plots and prediction–corrected visual predictive checks indicated a good fit of the observed IgG PK profiles. This integrated PK model has enabled a comprehensive understanding of IgG PK profiles for various immunoglobulin products, and will provide a framework for future investigations of IgG PK with different dosing regimens and in special or wider patient populations of interest.