Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

Abstract

Challenges in pediatric drug development include small patient numbers, limited outcomes research, ethical barriers, and sparse biosamples. Increasingly, pediatric drug development is focusing on extrapolation: leveraging knowledge about adult disease and drug responses to inform projections of drug and clinical trial performance in pediatric subpopulations. Pharmacokinetic‐pharmacodynamic (PK‐PD) modeling and extrapolation aim to reduce the numbers of patients and data points needed to establish efficacy. Planning for PK‐PD and biomarker studies should begin early in the adult drug development program. Extrapolation relies on the assumption that both the underlying disease and the mechanism of action of the drug used to treat that disease are similar in adults and pediatric subpopulations. Clearly, developmental changes in PK and PD need to be considered to enhance the quality of PK‐PD modeling and, therefore, increase the success of extrapolation. This article focuses on the influence of differences in PD between adults and pediatric subpopulations that are highly relevant for the use of extrapolation.

Physiologically‐Based Pharmacokinetic Modeling of Remdesivir and Its Metabolites to Support Dose Selection for the Treatment of Pediatric Patients With COVID‐19

“…These models minimize the need for unnecessary clinical trials while maximizing the use of available data by exploring PK, efficacy, and safety under various physiological conditions, bridging gaps from adults, if any, and aiding in efficient trial design. [19][20][21][22] Pediatric doses have traditionally been scaled from adult doses using the two most common methods for translating adult to pediatric PK: PBPK modeling and allometric scaling (including population PK-based approaches). 23,24 PBPK models provide more reliable predictions of plasma drug concentrations as they account for enzyme ontogeny and age-related changes in organ development and function.…”

“…Generally, in pediatric drug development, pharmacokinetic and pharmacodynamic (PK/PD) modeling and simulation are a vital first step in defining risk:benefit of a new medication. These models minimize the need for unnecessary clinical trials while maximizing the use of available data by exploring PK, efficacy, and safety under various physiological conditions, bridging gaps from adults, if any, and aiding in efficient trial design 19‐22 . Pediatric doses have traditionally been scaled from adult doses using the two most common methods for translating adult to pediatric PK: PBPK modeling and allometric scaling (including population PK–based approaches) 23,24 .…”

Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development

“…Where some uncertainty about the similarity of disease and/or response to intervention remains, this is referred to as partial extrapolation. In partial extrapolation, "confirmation of efficacy" is required, generally either through a single, controlled or uncontrolled efficacy, and safety trial, as well as evidence demonstrating a similar exposure-response relationship (28).…”

Pharmacogenomics for Drug Dosing in Children: Current Use, Knowledge, and Gaps

“…However, nascent modeling approaches such as physiologically based pharmacokinetic modeling that incorporate ontogeny and pharmacogenomic information have shown promising results 24,33,38,39 . Additional knowledge gaps exist broadly on whether similar drug concentrations and exposure as adults will achieve the same efficacy and/or toxicity endpoints in children 40 . Differences in physiology and disease processes in children might necessitate different doses and therefore different pharmacogenomics‐based dosing recommendations.…”