General clinical and methodological considerations on the extrapolation of pharmacokinetics and optimization of study protocols for small molecules and monoclonal antibodies in children

Abstract

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well‐designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state‐of‐the‐art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science.

The MILK study: Investigating intergenerational transmission of low-calorie sweeteners in breast milk

“…Therefore, to estimate the maturation function, data from children younger than 2 years are essential. The typical maturation function connects maturation to the postmenstrual age (PMA) and is expressed as [ 39 ]: MAT = PMA H / (PMA H + PMA_50 H ) …”

Innovative methodologies in paediatric drug development: A conect4children (c4c) special issue

“…As presented by the pharmacometrics group, in paediatric drug development, pharmacometrics is importantly used to extrapolate data from adults to children to describe pharmacokinetics in children. 5 It has been used to inform paediatric trial design, in particular, to support paediatric dosing. Both, the bottom-up approach using physiology-based pharmacokinetic models, integrating paediatric physiology, as well as top-down methods, using adult and juvenile paediatric data, or mixed approaches are explained and discussed.…”

“…The US FDA (United States Food and Drug Administration) defines Pharmacometrics as the science that quantifies drug, disease and trial information to aid efficient drug development and/or regulatory decisions. As presented by the pharmacometrics group, in paediatric drug development, pharmacometrics is importantly used to extrapolate data from adults to children to describe pharmacokinetics in children 5 . It has been used to inform paediatric trial design, in particular, to support paediatric dosing.…”