Pediatric physiology in relation to the pharmacokinetics of monoclonal antibodies

ABSTRACT

Introduction: Dose design for pediatric trials with monoclonal antibodies (mAbs) is often extrapolated from the adult dose according to weight, age, or body surface area. While these methods account for the size differences between adults and children, they do not account for the maturation of processes that may play a key role in the pharmacokinetics and/or pharmacodynamics of mAbs. With the same weight-based dose, infants and young children typically receive lower plasma exposures when compared to adults.

Areas covered: The mechanistic features of mAb distribution, elimination, and absorption are explored in detail and literature-based hypotheses are generated to describe their age-dependence. This knowledge can be incorporated into a physiologically based pharmacokinetic (PBPK) modeling approach to pediatric dose determination.

Expert opinion: As data from pediatric clinical trials become increasingly available, we have the opportunity to reflect on the physiologic drivers of pharmacokinetics, safety, and efficacy in children with mathematical models. A modeling approach that accounts for the age-related features of mAb disposition can be used to derive first-in-pediatric doses, design optimal sampling schemes for children in clinical trials and even explore new pharmacokinetic end-points as predictors of safety and efficacy in children.

KEYWORDS:

• Age-dependent
• monoclonal antibody
• pharmacokinetics
• physiology
• physiologically based pharmacokinetic modeling

Article highlights

This review explores the age-dependence of the physiologic processes governing the disposition of monoclonal antibodies in infants.

1. The fraction of extracellular fluid volume in the body decreases with age and provides large weight-normalized volumes of distribution in infants.

2. Extravasation of antibodies into tissues occurs quickly in infants as they have a large capillary surface area per unit volume available for plasma protein exchange and a large proportion of ‘leaky’ tissues, where capillary permeability is highest.

3. Intracellular metabolism and elimination during transcytosis may be increased due to low expression of FcRn—the neonatal salvage receptor—and the relatively high concentration of endogenous IgG competing for FcRn binding after birth.

A fast rate of lymph flow in infants drives a fast rate of absorption after extravascular administration.

Acknowledgments

P Malik would like to acknowledge Dr. Anita Cheng for her clinical perspective during manuscript writing.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded