Effects of the FcRn developmental pharmacology on the pharmacokinetics of therapeutic monoclonal IgG antibody in pediatric subjects using minimal physiologically-based pharmacokinetic modelling. Issue 7 (3rd October 2018)

• Record Type: Journal Article
• Authors: Hardiansyah, Deni; Ng, Chee Meng
• Is Part Of: MAbs. Volume 10:Issue 7(2018)
• Page Start: 1144
• Page End: 1156
• Publication Date: 2018-10-03
• Subjects: Antibody -- mPBPK model -- pediatric -- FcRn receptor -- Extravasation rate -- IgG synthesis rate; Monoclonal antibodies -- Therapeutic use -- Periodicals; Monoclonal antibodies -- Periodicals; Antibodies, Monoclonal -- Periodicals; 616.0798
• DOI: 10.1080/19420862.2018.1494479
• Languages: English
• ISSNs: 1942-0862

Abstract

ABSTRACT: The aim of this study was to investigate neonatal Fc receptor (FcRn) concentration developmental pharmacology in adult and pediatric subjects using minimal physiologically-based pharmacokinetic (mPBPK) modelling. Three types of pharmacokinetic (PK) data for three agents (endogenous/exogenous native IgG, bevacizumab and palivizumab) were used. The adult group contained six subjects with weights from 50 to 100 kg. For pediatric subjects, seven age groups were assumed, with five subjects each having the weight of 95%, 75%, 50%, 25% and 5% percentile of the population. A first evidence-based rating system to evaluate the quality of the source data used to derive pediatric-specific mPBPK model parameter was proposed. A stepwise approach was used to examine the best combination of age/weight effect on the parameters of the mPBPK model in adult and pediatric subjects. IgG synthesis rate (Ksyn ), extravasation rate (ER) and FcRn were fitted simultaneously to the PK of bevacizumab and native-IgG in both adult and pediatric. All fitting showed good fits based on the graphs and the coefficient of variation of the fitted parameters (< 50%). Estimated weight-normalized Ksyn increased while weight-normalized FcRn and ER decreased with increasing age. The age and weight effect on FcRn were successfully estimated from the data. The final mPBPK model developed with native IgG and bevacizumab was able to predict the PK of palivizumab in pediatric subjects. Implementation of the mPBPK model enables us to analyze the relationships of age, weight, FcRn, ER and Ksyn in both adult and pediatric subject. This information may benefit the understanding of complex interaction between the FcRn developmental pharmacology and PK parameters, and improve the prediction of the antibody disposition in pediatric subjects.