Pharmacokinetics and Pharmacokinetic–Pharmacodynamic Relationships of Monoclonal Antibodies in Children

Abstract

Monoclonal antibodies (mAbs) constitute a therapeutically and economically important drug class with increasing use in both adult and paediatric patients. The rather complex pharmacokinetic and pharmacodynamic properties of mAbs have been extensively reviewed in adults. In children, however, limited information is currently available. This paper aims to comprehensively review published pharmacokinetic and pharmacokinetic-pharmacodynamic studies of mAbs in children. The current status of mAbs in the USA and in Europe is outlined, including a critical discussion of the dosing strategies of approved mAbs. The pharmacokinetic properties of mAbs in children are exhaustively summarised along with comparisons to reports in adults: for each pharmacokinetic process, we discuss the general principles and mechanisms of the pharmacokinetic/pharmacodynamic characteristics of mAbs, as well as key growth and maturational processes in children that might impact these characteristics. Throughout this review, considerable knowledge gaps are identified, especially regarding children-specific properties that influence pharmacokinetics, pharmacodynamics and immunogenicity. Furthermore, the large heterogeneity in the presentation of pharmacokinetic/pharmacodynamic data limited clinical inferences in many aspects of paediatric mAb therapy. Overall, further studies are needed to fully understand the impact of body size and maturational changes on drug exposure and response. To maximise future knowledge gain, we propose a 'Guideline for Best Practice' on how to report pharmacokinetic and pharmacokinetic-pharmacodynamic results from mAb studies in children which also facilitates comparisons. Finally, we advocate the use of more sophisticated modelling strategies (population analysis, physiology-based approaches) to appropriately characterise pharmacokinetic-pharmacodynamic relationships of mAbs and, thus, allow for a more rational use of mAb in the paediatric population.

The underlying inflammatory chronic disease influences infliximab pharmacokinetics

“…44 A recent review suggests that differences between adults and children may be explained by specific factors (such as target-antigen burden), a hypothesis which deserves further investigation. 45 Of note, the influence of age on absorption was reported for an anti-interleukin 4 receptor monoclonal antibody administered subcutaneously, the absorption rate decreasing with age. 46 The infliximab pharmacokinetic parameters estimated in our study were used to predict the distribution of infliximab trough concentrations at steady-state and compare them with cut-off concentrations predictive of good clinical response.…”

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

“…While it is yet to be explored, PBPK modeling may even offer adequate pediatric PK predictions for molecules that are subject to target‐mediated drug disposition and nonlinear elimination. As already mentioned, children, and especially premature infants, typically achieve much lower plasma exposures to biologic drugs than adults with the same milligram/kilogram doses . Since a PBPK model accounts for target‐binding and nonlinear elimination mechanistically, such an approach would theoretically be able to classify when the drug would enter the linear CL range in children.…”

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 …”

“…For most therapeutic proteins, body weight–normalized clearance and volume of distribution are higher in children or have similar values in children and adults. To fully understand the differences and similarities in the pharmacokinetics of therapeutic antibodies between adults and children, further research is needed …”