Pharmacokinetic models for FcRn-mediated IgG disposition.
The objectives were to review available PK models for saturable FcRn-mediated IgG disposition, and to explore an alternative semimechanistic model. Most available empirical and mechanistic PK models assumed equal IgG concentrations in plasma and endosome in addition to other model-specific assumptions. These might have led to inappropriate parameter estimates and model interpretations. Some physiologically based PK (PBPK) models included FcRn-mediated IgG recycling. The nature of PBPK models requires borrowing parameter values from literature, and subtle differences in the assumptions may render dramatic changes in parameter estimates related to the IgG recycling kinetics. These models might have been unnecessarily complicated to address FcRn saturation and nonlinear IgG PK especially in the IVIG setting. A simple semimechanistic PK model (cutoff model) was developed that assumed a constant endogenous IgG production rate and a saturable FcRn-binding capacity. The FcRn-binding capacity was defined as MAX, and IgG concentrations exceeding MAX in endosome resulted in lysosomal degradation. The model parameters were estimated using simulated data from previously published models. The cutoff model adequately described the rat and mouse IgG PK data simulated from published models and allowed reasonable estimation of endogenous IgG turnover rates.
Department of Clinical Pharmacology, Genentech Inc., 1 DNA Way, MS 463A, South San Francisco, CA 94080, USA. xiao.jim@gene.com
Jim J
JJ
Xiao
D000818:Animals; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D008954:Models, Biological; D010599:Pharmacokinetics; D011961:Receptors, Fc / Q000378:metabolism*
D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; C100688:Fc receptor, neonatal