Population Pharmacokinetic Modeling and Simulation of Immune Globulin Intravenous (Human), 10% Liquid in Pediatric and Adult Patients with Primary Immune Deficiency Disorders

Background Immune globulin intravenous (human), 10% liquid (IVIG) (BIVIGAM®) is approved for use in patients with primary immunodeficiency disorders (PIDD). To support a post-marketing requirement for pharmacokinetic (PK)-focused assessments in pediatric patients aged 2-16 years, a model-informed drug development approach was used to increase number of patients to improve estimation of factors affecting drug exposure and evaluate application of allometry for this plasma-derived therapeutic. Objectives 1) Characterize total immunoglobulin G (IgG) PK of BIVIGAM® in children and adolescents with PIDD using a population PK (PPK) modeling approach; 2) Quantify the impact of age or body weight on the PKs of IVIG; and 3) Compare simulated exposure of BIVIGAM® between pediatric and adult subjects to support supplemental PK and efficacy. Methods A PPK model was developed using pooled adult and pediatric data from 2 studies in 79 subjects (phase 3 study Nabi-7101 [NCT00538915; n = 63] and phase 4 study 994 [NCT03164967; n = 16]) with 3, 9, 13, and 54 subjects in age-groups of 2 to <6 years, 6 to <12 years, 12 to 16 years, and >16 years, respectively. Covariate analysis evaluated associations between age and body weight with IgG clearance. Fixed and estimated allometry were used to simulate and conservatively extrapolate therapeutic efficacy. Results Serum IgG PK of IVIG following intravenous infusion was well characterized using a 2-compartment model, based on 1243 IgG concentrations, with body weight confirmed as the sole covariate affecting total IgG clearance and volumes of distribution. Model-based clearance values when estimating allometric exponents were comparable across age-group categories (Table 1). Simulations performed for every 4-week dosing cycles for both model types (Figure 1) suggested ≥90% of subjects would achieve ≥5 g/L trough levels (minimum recommended level) for a mid-range dose of 500 mg/kg every 4 weeks. Table 1. Distribution of post hoc clearance values (dL/day/kg) for estimated and fixed allometric exponents models Estimated Allometry Fixed Allometry Age Group N Mean CV(%) Mean CV(%) 2 to <6 years 3 0.0149 6.7 0.0185 22.2 6 to <12 years 9 0.0146 15.8 0.0165 27.9 12 to ≤16 years 13 0.0137 21.2 0.0143 24.5 >16 years 54 0.0145 24.8 0.0147 25.2 Abbreviations: CL=clearance; CV=coefficient of variation; N=number of subjects with available information. Figure 1. Simulated total trough IgG concentration following 4-week cycles of BIVIGAM® for (A) estimated and (B) fixed allometric exponents models. Note: The box starts in the quartile (25%) and ends in the third quartile (75%) of trough concentration in each age-group. The solid line in each box represents the median of trough concentration in each age-group. The dots represent the subjects with trough concentration more than 1.5 × IQR from the closest edge of the box. Abbreviations: IgG = immunoglobulin G; IQR = interquartile range. Conclusions Simulation from models with estimated and fixed allometric predicted trough IgG levels for a virtual population of 1000 subjects across pediatric age-groups with the recommended BIVIGAM® dosage of 300 to 800 mg/kg and confirmed clinically acceptable trough IgG levels (∼7 g/L) would be achieved to support dosing recommendations for patients ≥2 years of age with PIDD.