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

• Published in: International immunopharmacology 2022-12, Vol.113 (Pt A), p.109331, Article 109331
• Main Authors: Li, Zhaoyang, Follman, Kristin, Freshwater, Ed, Engler, Frank, Yel, Leman
• Format: Article
• Language: English
• Subjects: Administration, Intravenous; Biological Availability; Disease Progression; Humans; Immunoglobulin G; Immunoglobulins, Intravenous - therapeutic use; Intravenous immunoglobulin; Model-informed drug development; Population pharmacokinetics; Primary immunodeficiencies; Subcutaneous immunoglobulin
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2022.109331

•The popPK of IVIG, SCIG and fSCIG were characterized using data from 8 PID studies.•The popPK model characterized IgG PK profiles, with a good fit of the observed data.•Endogenous IgG and product effect on SC bioavailability were estimated.•Lean body mass was included as an allometric scalar on key PK parameters.•The integrated model will support new IgG PK studies in wider patient population. 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