Model‐Informed Pediatric Drug Development: Application of Pharmacometrics to Define the Right Dose for Children

Abstract

One of the biggest challenges in pediatric drug development is defining a safe and effective dose in pediatric populations, which span across a wide age and development range from neonates to adolescents. Model‐informed drug development approaches are particularly suited to address knowledge gaps including data leveraging to increase the success of pediatric studies. Considering the often limited number of patients available for study and logistic difficulties to collect the necessary data in pediatric populations, the application of pharmacometrics and modeling and simulation techniques can improve clinical trial efficiency, increase the probability of regulatory success, and optimize therapeutic individualization in support of dedicated trials. This review describes the state of pediatric model‐informed drug development to define the right dose for children and provides suggestions for future development.

Off‐Label, but on‐Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy

“…However, these studies may include less children or may be less complicated when modeling and simulation can support their design. 40 , 41 , 42 In addition, electronic health records host a pool of RWD generated by clinical practice, such as patient characteristics, laboratory findings, routinely collected blood concentrations, and pharmacodynamic outcomes. The usability of RWD, however, is still hindered by the diversity of systems that capture these data and most importantly the temporal relation to these data.…”

“…Pharmacokinetic (PK) studies may still be needed to verify extrapolated doses from adults, as unexpected variation in the mechanisms involved in drug disposition may affect drug disposition in children of different ages. However, these studies may include less children or may be less complicated when modeling and simulation can support their design 40–42 . In addition, electronic health records host a pool of RWD generated by clinical practice, such as patient characteristics, laboratory findings, routinely collected blood concentrations, and pharmacodynamic outcomes.…”

What did we learn (and did not learn) from the pediatric direct oral anticoagulant trials, and how might we better design pediatric anticoagulant trials in the future?

“…Dose finding studies are ethically and methodically challenging because short-term drug administration provides little clinical benefit to the patient, and there are barriers to venipunctures and limited blood volumes available from small children. Sophisticated methods are now available to quantify existing knowledge from adults and age-specific physiological data, such as modeling and simulation using physiologically based PK models or population PK models [ 36 ]. Such models allow the prediction of age/maturation-specific doses, estimation of PK/PD profiles, and thereby, to optimize sampling schemes, sparse sampling, and minimize sample size requirements.…”

Study of Drugs: Antibiotic and Study Mechanism and Adverse Effects

“…The study of pharmaceuticals, or pharmacology, covers all aspects of a drug's use in medicine, such as its mechanism of action, physical and chemical characteristics, metabolism, treatments, and toxicity. In addition to providing a general review of the many medication types used in the treatment and prevention of human illnesses, this article concentrates on the principles of pharmacological action [1,2].…”