Effects of the FcRn developmental pharmacology on the pharmacokinetics of therapeutic monoclonal IgG antibody in pediatric subjects using minimal physiologically-based pharmacokinetic modelling

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 (K), 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 K 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 K 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.

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

“…Both of these moderate the availability of the free FcRn parameter. Previous minimal PBPK modeling work by Hardiansyah and Ng fully attributed the unique elimination profile of mAbs in children to altered FcRn expression. However, similar patterns of pediatric exposure are observed for other protein‐based drugs that do not bind to FcRn, such as erythropoietin‐stimulating agents and coagulation factor concentrates .…”

“…The availability of FcRn for intracellular salvage is a key determinant of plasma half‐life. Some preliminary data may suggest lower FcRn concentrations in children, though no definitive argument can yet be made . Three studies have examined FcRn expression in neonatal subjects relative to adults .…”

“…The US Food and Drug Administration has stressed the importance of incorporating these physiologic parameters into a PBPK modeling framework to support pediatric drug development for mAbs and Fc‐fusion proteins . To date, only one effort has been made to explore the PK of mAbs in pediatrics with a minimal PBPK modeling approach …”

Predictive Pediatric Modeling and Simulation Using Ontogeny Information

“…It was further hypothesized that there is faster extravasation in young children due to a relatively higher ratio of tissues with leaky vascular endothelium and higher capillary density in young children . A minimal PBPK model was recently used to study the developmental pharmacokinetics of antibodies . The FcRn concentration, the synthesis rate of endogenous IgG, and the extravasation rate were fitted to endogenous IgG levels and to bevacizumab pharmacokinetic data, which were simulated for different age groups from a published population pharmacokinetic analysis.…”

Physiologically‐Based Pharmacokinetic Modeling vs. Allometric Scaling for the Prediction of Infliximab Pharmacokinetics in Pediatric Patients

“…The mechanisms governing the PKs of large molecules are not at all similar to those of small molecules . Platform PBPK models for large molecules in adults have emerged in the last 7 years, and, to date, only one minimal PBPK modeling effort has been made to characterize PKs in children . We continue the exploration with a whole‐body approach to the PKs of infliximab in children because a large amount of pediatric PK data are available for this purpose in published literature.…”