Population pharmacokinetics of immunoglobulin intravenous preparation in very low birth weight neonates

Abstract

BackgroundImmunoglobulin products are widely used across multiple therapeutic areas such as immunodeficiency syndromes, infection and autoimmune diseases. The pharmacokinetics (PK) of immunoglobulins are well characterized in adults, but very little is known about the PK of immunoglobulins in neonates and infants (<2 years of age). ObjectiveThe objectives of the present study were: (1) characterize the PK of immunoglobulin intravenous preparation using model-independent (non-compartmental analysis), and (2) develop and evaluate a population PK model with extensive blood samples (8 blood samples) and sparse blood samples (2–3 blood samples). MethodImmunoglobulin G (IgG) concentration versus time data from very low birth weight neonates (n = 20) following intravenous administration were analyzed using nonlinear mixed effect modeling and non-compartmental approaches. Population pharmacokinetic models were developed from extensive and sparse sampling schemes. Models were evaluated based on the difference in objective function, goodness-of-fit plots and simulation based visual predictive check analysis. ResultsA non-compartmental analysis of IgG from neonates (bodyweight range 0.78–1.38 kg) indicated an average clearance of 3.0 ± 2.1 mL/day and volume of distribution at steady state 68 ± 25 mL. The population pharmacokinetic model from extensive sampling adequately described concentration- time data with mean clearance (2.7 mL/day), volume of central compartment (8.7 mL) and peripheral compartment (60 mL). The clearance and volume of distribution estimates using sparse sampling model (1 pre-and 2 post-dose blood samples) were comparable with extensive sampling. ConclusionOur study provides important bridging data in scaling PK and dosing of immunoglobulins across a wide age range.