Pharmacokinetic Model Based Sensitivity Analysis to Lower Recruitment Burden for Young Children Requiring Intravenous Immunoglobulin G Replacement.

To support a post-marketing requirement for pharmacokinetic (PK)-focused assessments in patients ages 2-16 years, a model-informed drug development approach was used to overcome enrollment barriers in recruiting pediatric subjects with primary immune deficiency (PID) disorders under Age 6 in a Phase 4 pediatric study. Models (1) characterized total immunoglobulin G (IgG) PK of Immune Globulin Intravenous [Human], 10% Liquid [IVIG] (BIVIGAM) in children and adolescents with PID; (2) quantified the impact of age and body weight; and (3) compared simulated exposure of IVIG between pediatric and adult subjects. Models were developed using pooled adult and pediatric data from 2 Phase 3/4 studies in 79 subjects (1243 IgG levels) with 3, 9, 13, and 54 subjects 2 to < 6 years, 6 to < 12 years, 12-16 years, and > 16 years, respectively. Serum IgG PK of IVIG following intravenous infusion was characterized using a 2-compartment PK model with body weight on total IgG clearance and volumes of distribution. Model-based clearance values when estimating allometric exponents were comparable across age-group categories. Simulations predicted trough IgG levels for a virtual population of subjects for recommended IVIG 10% dosages of 300-800 mg/kg. Fixed and estimated allometric scaling allowed conservative extrapolation with simulations showing ≥ 90% of subjects would achieve trough levels ≥ 5 g/L (minimum recommended level) for a mid-range dose of 500 mg/kg. Modeling and simulation were integral in confirming achievement of clinically acceptable trough IgG levels (~7 g/L) to support supplemental PK, efficacy, and dosing recommendations for patients ≥ 2 years of age.Trail Registration: NCT00538915 and NCT03164967.