Role of Model‐Informed Drug Development in Pediatric Drug Development, Regulatory Evaluation, and Labeling

Abstract

The unique challenges in pediatric drug development require efficient and innovative tools. Model‐informed drug development (MIDD) offers many powerful tools that have been frequently applied in pediatric drug development. MIDD refers to the application of quantitative models to integrate and leverage existing knowledge to bridge knowledge gaps and facilitate development and decision‐making processes. This article discusses the current practices and visions of applying MIDD in pediatric drug development, regulatory evaluation, and labeling, with detailed examples. The application of MIDD in pediatric drug development can be broadly classified into 3 categories: leveraging knowledge for bridging the gap, dose selection and optimization, and informing clinical trial design. In particular, MIDD can provide evidence for the assumption of exposure‐response similarity in bridging existing knowledge from reference to target population, support the dose selection and optimization based on the “exposure‐matching” principle in the pediatric population, and increase the efficiency and success rate of pediatric trials. In addition, the role of physiologically based pharmacokinetics in drug‐drug interaction in children and adolescents and in utilizing ontogeny data to predict pharmacokinetics in neonates and infants has also been illustrated. Moving forward, MIDD should be incorporated into all pediatric drug development programs at every stage to inform clinical trial design and dose selection, with both its strengths and limitations clearly laid out. The accumulated experience and knowledge of MIDD has and will continue to drive regulatory policy development and refinement, which will ultimately improve the consistency and efficiency of pediatric drug development.

Impact of Hepatic CYP3A4 Ontogeny Functions on Drug–Drug Interaction Risk in Pediatric Physiologically‐Based Pharmacokinetic/Pharmacodynamic Modeling: Critical Literature Review and Ivabradine Case Study

“…7 Although PBPK-based prediction of DDIs in adults is widely accepted, 11 this application remains sparse in children. 12,13 As pediatric DDI studies are particularly challenging for ethical and practical reasons, mechanistic modeling could be an ideal alternative. 14 However, the lack of understanding and/ or knowledge in maturation of certain processes can limit the extrapolative power and confidence in this approach.…”

The use of extrapolation based on modeling and simulation to support high‐dose regimens of ceftaroline fosamil in pediatric patients with complicated skin and soft‐tissue infections

“…[34][35][36] MIDD, including the use of modeling and simulation to predict clinical outcomes and evidence of effectiveness, is integral to antibacterial development as true dose ranging efficacy studies for drugs to treat serious infections cannot ethically be conducted. [37][38][39] MIDD has been widely used to support dose selection, optimizing and informing clinical trial design, particularly in pediatric drug development due to challenges in subject recruitment and limitations of blood sample collection. 37 In the current analysis the population PK of ceftaroline fosamil and ceftaroline in pediatric subjects (birth to <18 years) with CAP, cSSTI, or suspected/confirmed infection, and healthy adult volunteers, adult subjects with various degrees of renal function, and adults with CAP or cSSTI, were adequately characterized using a simultaneous modeling approach with two-compartment disposition models.…”

“…[37][38][39] MIDD has been widely used to support dose selection, optimizing and informing clinical trial design, particularly in pediatric drug development due to challenges in subject recruitment and limitations of blood sample collection. 37 In the current analysis the population PK of ceftaroline fosamil and ceftaroline in pediatric subjects (birth to <18 years) with CAP, cSSTI, or suspected/confirmed infection, and healthy adult volunteers, adult subjects with various degrees of renal function, and adults with CAP or cSSTI, were adequately characterized using a simultaneous modeling approach with two-compartment disposition models. As there were no significant patient or indication effect differences on CLc and Vcc for cSSTI…”

Drug Dosing Recommendations for All Patients: A Roadmap for Change

“…Therefore, pediatric labeling changes for some priority indications may not occur. Based on data from completed studies, there is now a reasonably good ability to predict pediatric PKs for major clearance pathways 26 . Pharmaceutical companies have an estimated 680% median return on investment for doing requested pediatric studies as a result of gaining 6 months of additional patent exclusivity 32 .…”