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Pharmacokinetic Model Based Sensitivity Analysis to Lower Recruitment Burden for Young Children Requiring Intravenous
Todd Dumas1, Shahram Mehr1, Rebecca Avila2
1Certara USA, Radnor, Pennsylvania, USA.
Insights
Model-informed drug development confirmed adequate immunoglobulin levels in pediatric patients with primary immune deficiency (PID) using Immune Globulin Intravenous [Human], 10% Liquid [IVIG]. This approach supports dosing recommendations for children aged 2 and older.
Area of Science:
- Pharmacokinetics
- Immunology
- Pediatric Pharmacology
Background:
- Post-marketing studies for Immune Globulin Intravenous [Human], 10% Liquid [IVIG] (BIVIGAM) require pharmacokinetic (PK) assessments in pediatric patients aged 2-16 years.
- Recruiting young children (under 6) with primary immune deficiency (PID) disorders for clinical trials presents enrollment challenges.
Purpose of the Study:
- To characterize the PK of IVIG in pediatric patients with PID.
- To quantify the influence of age and body weight on IVIG PK.
- To compare simulated IVIG exposure between pediatric and adult populations.
Main Methods:
- A model-informed drug development approach was utilized, employing pooled data from adult and pediatric subjects (N=79) across two Phase 3/4 studies.
- A 2-compartment PK model was developed, incorporating body weight to describe total IgG clearance and distribution volumes.
- Simulations were performed to predict trough IgG levels for virtual pediatric populations at various IVIG dosages.
Main Results:
- The PK of IVIG in pediatric patients with PID was successfully characterized, with model-based clearance comparable across age groups.
- Simulations indicated that 90% of subjects would achieve recommended trough IgG levels (≥5 g/L) with a 500 mg/kg dose.
- The model confirmed achievement of clinically acceptable trough IgG levels (~7 g/L) in pediatric patients aged 2 years and older.
Conclusions:
- Model-informed drug development effectively overcame pediatric enrollment barriers for PK assessments.
- The study provides robust PK, efficacy, and dosing recommendations for IVIG in pediatric patients aged 2 years and above with PID.
- This approach supports the post-marketing requirements for IVIG in a pediatric population.
Abstract:
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.
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