Monoclonal Antibodies and Fc‐Fusion Proteins for Pediatric Use: Dosing, Immunogenicity, and Modeling and Simulation in Data Submitted to the US Food and Drug Administration

Abstract

The experience with the use of monoclonal antibodies and Fc‐fusion proteins (mAb/Fc) in the pediatric population is limited. The objective of this study is to review those factors impacting the clinical efficacy and product safety of mAb/Fc products in pediatric patients during drug development. We reviewed the list of biologic products in the US Food and Drug Administration's Purple Book as of March 2018 with a focus on mAb/Fc products that are indicated for use in both adults and pediatric patients. Of 68 mAb/Fc products in the Purple Book (excluding biosimilars), 20 products have approved indications in both adults and children. Thirteen products had concurrent approval for both adult and pediatric populations. The sample size of pediatric studies generally ranged from approximately 2% to 70% of the sample size of adult studies with the same indication. In general, pediatric dosing regimens were found to be more based on body weight and weight tiered than the regimens for adults. Modeling and simulation techniques comprised mainly population pharmacokinetic and pharmacodynamic models. A review of the immunogenicity incidence did not reveal any notable difference in the 5 products having data on both pediatric and adult patients. In conclusion, most of the mAb/Fc products have a different weight‐based dosing regimen for pediatric patients versus adults. An understanding of the comparative experience in drug development for mAb/Fc products between adult and pediatric patients coupled with the application of advanced modeling and simulation methods should assist future development of new mAb/Fc products for pediatric patients.

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

“…Preterm infants are gaining increased therapeutic attention in drug development for mAbs and IgG products against infectious syndromes of prematurity (eg, HIV, respiratory syncytial virus, cytomegalovirus, staphylococcal sepsis). The US Food and Drug Administration recently highlighted the need for pediatric PBPK modeling efforts to support drug development and clinical trial design for this vulnerable population, as is commonly done in the context of small molecules . In response, we begin the first whole‐body PBPK modeling assessment of mAbs in preterm infants, with pagibaximab, palivizumab, MEDI8897, and IVIG as working examples.…”

“…Our recent review highlights the key physiologic drivers of this phenomenon in pediatrics . 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

“…Some of the knowledge implemented in PBPK models for small molecules is also relevant for therapeutic proteins, such as the age‐dependent change of body composition regarding extracellular volume and blood plasma volume or the ontogeny of the GFR for therapeutic proteins that are small enough to be filtered. However for many mechanisms influencing the pharmacokinetics of therapeutic proteins, there is only limited information regarding their maturation and ontogeny …”

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

“…Physiologically‐based pharmacokinetic (PBPK) modeling and allometric scaling are the two most common methods for translating knowledge of adult pharmacokinetics (PKs) to the pediatric space for the planning of pediatric clinical trials . Although drug developers and regulatory agencies alike maintain high confidence in both methods for small molecule drugs, little is known about the performance and utility of either method for large molecule drugs . Here, we evaluate the two approaches for the prediction of large molecule PKs in pediatric patients with infliximab as a working example, because plenty of adult and pediatric data are available in published literature for the exercise.…”

“…Monoclonal antibodies are a rapidly expanding drug class, and pediatric investigations are well underway. The FDA has recently highlighted the gaps in modeling and simulation efforts to support pediatric drug approvals . By completing this work, we aim to assess the confidence with which PBPK modeling and/or allometric scaling can be applied in the context of pediatric drug development and clinical trial planning.…”