Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting the Effects of Anti-FcRn Therapy on the Disposition of Endogenous IgG in Humans.

This work scaled up a previously developed physiologically based pharmacokinetic model to predict the effects of anti-FcRn agents on the disposition of endogenous IgG in human subjects. Simulations were performed with the scaled model to predict the effects of single- and multiple-dose administration of anti-FcRn monoclonal antibodies (1-256 mg/kg) and high-dose intravenous immune globulin (0.4-2 g/kg). The model was evaluated for prediction accuracy through comparison to the effects of rozanolixizumab, an anti-FcRn monoclonal antibodies under current clinical evaluation, on the disposition of endogenous IgG in healthy human subjects. The model provided reasonably accurate predictions of the effects of rozanolixizumab. Prediction errors for the maximum reduction in endogenous IgG concentrations were -8.50% (90% model prediction interval: -14.0% to 1.44%), 3.33% (90% model prediction interval: -13.9% to 21.2%), and 6.85% (90% model prediction interval: -35.2% to 10.5%) for rozanolixizumab doses of 1, 4, and 7 mg/kg, respectively. Model simulations predict that anti-FcRn therapies will exhibit greater dose potency in healthy volunteers than in patients with elevated IgG production rates (e.g., as typically found in autoimmune disease). The model appears to have potential for use in assessing and predicting novel dosing strategies for anti-FcRn therapies.