Background: Predominantly antibody deficiency (PAD) is a rare and serious medical condition due to its likelihood to cause fatal infections. Affected patients require life-long immunoglobulin replacement therapy (IRT) and the adequacy is determined by the IgG trough at steady state in relation to clinical response. There is considerable interpatient variability in the pharmacokinetics (PK) of intravenous immunoglobulin G (IVIG), causing difficulty in optimizing individual dosage regimen. This study aims to estimate the population PK parameters of IVIG and to investigate the impact of genetic polymorphism of the FcRn gene and clinical variability on the PK of IVIG in patients with PAD.
Methods: Patients were recruited from four hospitals. Clinical data were recorded and blood samples were taken for PK and genetic studies. Population PK parameters were estimated by nonlinear mixed-effects modeling in Monolix®. Models were evaluated using the difference in objective function value, goodness-of-fit plots, visual predictive check and bootstrap analysis. Monte Carlo simulation was conducted to evaluate different dosing regimens for IVIG.
Results: A total of 30 blood samples were analyzed from 10 patients. The immunoglobulin G concentration data were best described by a one-compartment model with linear elimination. The final model included both volume of distribution (Vd) and clearance (CL) based on patient’s individual weight. Goodness-of-fit plots indicated that the model fit the data adequately, with minor model mis-specification. Genetic polymorphism of the FcRn gene and the presence of bronchiectasis did not affect the PK of IVIG. Simulation showed that dosing intervals of 3 to 4-weekly was sufficient to maintain IgG levels of 5 g L-1, with more frequent intervals needed to achieve higher trough levels.
Conclusions: Body weight significantly affects the PK parameters of IVIG. Genetic and other clinical factors investigated did not affect the disposition of IVIG.
- Landersdorfer CB, Bexon M, Edelman J, Rojavin M, Kirkpatrick MJ, Lu J, et al. Pharmacokinetic modeling and simulation of biweekly subcutaneous immunoglobulin dosing in primary immunodeficiency. Postgrad Med. 2013; 125: 53–61.
- Gouilleux-Gruart V, Chapel H, Chevret S, Lucas, M, Malphettes M, Fieschi C, et al. Efficiency of immunoglobulin G replacement therapy in common variable immunodeficiency: Correlations with clinical phenotype and polymorphism of the neonatal Fc receptor. Clin Exp Immunol. 2012; 171: 186-94.
- Litzman J. Influence of FCRN expression on lung decline and intravenous immunoglobulin catabolism in common variable immunodeficiency patients. Clin Exp Immunol. 2014; 178: 103–4.